Modified release formulations and uses thereof

ABSTRACT

Provided are modified release compositions in a solid oral dosage form comprising amisulpride in the form of an unequal mixture of (R)-amisulpride and (S)-amisulpride, or pharmaceutically acceptable salts thereof, where the amount of (R)-amisulpride is greater than the amount of (S)-amisulpride, and medicaments comprising the same used for the treatment of various diseases and disorders, and methods of using same for the treatment of various diseases and disorders, including, but not limited to, dosage regimens. In addition, provided are formulations employing polymorphs of enantiomeric amisulpride.

FIELD OF THE INVENTION

The present disclosures relate to modified release pharmaceuticalcompositions of non-racemic amisulpride and methods and uses thereof.

BACKGROUND

Amisulpride is a member of the chemical class benzamide, and has thechemical name4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2-methoxy-benzamide.The chemical structure of amisulpride is as follows:

There is a need for better treatments of psychiatric and mood disorders,including schizophrenia, depression, bipolar disorder and in particulardepression associated with bipolar disorder. For example, psychiatristsindicate that about 25% of patients across all bipolar disorders arerefractory during a manic episode, while about 70% are refractory duringa depressive episode. Thus, there is a need for drugs that remitdepressive symptoms in bipolar patients.

Dopamine receptor antagonists are one class of drugs used to treatpsychiatric disorders, however efficacious D₂ occupancy levels are alsorelated to deleterious side effects. A need also therefore exists forcentral nervous system drugs (CNS) and in particular psychiatric drugsfor the treatment of depression and diseases and disorders with adepressive component, that provide a therapeutic effect with no orreduced side effects and in particular side effects associated withdopamine D₂ receptor occupancy.

Racemic amisulpride is sold under the tradename Solian® as 400 mg tabletand as a solution for the treatment of acute and chronic schizophrenicdisorders, in which positive symptoms (such as delusions,hallucinations, thought disorders) and/or negative symptoms (such asblunted affect, emotional and social withdrawal) are prominent,including patients characterized by predominant negative symptoms, witha recommended total daily dose of 400-800 mg. However, movement relatedadverse events including tremor, rigidity, hypokinesia, hypersalivation,akathisia, dyskinesia are listed as “very common” in the label forracemic amisulpride in the 400-800 mg/day dosage range. Suchextrapyramidal symptoms are commonly associated with antipsychotic drugsemploying dopamine receptor blockade. Typically, extrapyramidal symptomsare observed at high dopamine receptor occupancy, e.g., at about 70-75%occupancy.

Other adverse events and side effects associated with amisulprideinclude prolongation of the QT interval and increase in prolactin whichmay lead to galactorrhoea, amenorrhoea, gynaecomastia, breast pain,erectile dysfunction. The QT interval represents the duration ofventricular depolarization and subsequent repolarization. QT intervalprolongation creates an electrophysiological environment that favors thedevelopment of ventricular tachyarrhythmias, the most clinicallysignificant being Torsades de Pointes (TdP) which can lead toventricular fibrillation and sudden cardiac death. Patients taking oneor more than one QT prolonging drug concomitantly, have an enhanced riskof TdP. Therefore, there is need for better psychiatric drugs and drugformulations with reduced side effects such as QT interval prolongation.

Thus there is a need for an amisulpride composition which has reducedadverse events and a greater safety profile. There is a further need foran amisulpride composition which can effectively treat bipolar symptomsaccompanied with depression more effectively than current compositions.

SUMMARY

These and other objectives make use of the unexpected discovery by theinventors of modified release formulations of non-racemic amisulpridecompositions that provide a therapeutic effect that is the substantiallythe same as that of an immediate release formulation of the sameamisulpride dosage, but with reduced side effects. The present inventorshave discovered modified release pharmaceutical formulations ofamisulpride that can provide substantially the same efficacy ascomparable immediate release formulations at both lower blood plasmamaximum concentrations (Cmax) and total blood plasma concentration(AUC). Thus, in various aspect and embodiments, provided are modifiedrelease pharmaceutical formulations of amisulpride with substantiallythe same efficacy as comparable immediate release formulations but withreduced adverse events and side effects.

It has further been discovered by the inventors that the behavior ofamisulpride observed in their studies cannot be accounted for with, andis counter-intuitive to, traditional models. The studies have shown thatamisulpride exhibits: (1) time-hysteresis: the clearance from plasma israpid compared to the washout of brain occupancy, (2) dose-response:occupancy increases with dose and receptor binding is not saturated, and(3) lack-of-accumulation: brain occupancy does not accumulatesubstantially to steady state. The inventors have developed a noveldistribution model, that accurately captures the three key observationsabove: time-hysteresis, dose-response, and lack-of-accumulation; and howthe reduced blood plasma exposures with modified release (MR)formulations in the various embodiments of the present inventions canstill attain brain D2 receptor occupancies equivalent to those observedfor immediate release (IR) formulations.

In various aspects and embodiments, provided are modified releaseformulations of amisulpride that can provide an occupancy of dopamine D2receptors (as a measure for antipsychotic drug efficacy, e.g., in thetreatment of mania, depression, bipolar disorders, schizophrenia, etc.)that is at least 85% of the dopamine D2 receptors occupancy achieved byan immediate release composition having the same total daily amount ofamisulpride but with a blood plasma Cmax of amisulpride that is lessthan about 80% of the Cmax and an AUC from 0 to 24 hours afteradministration (AUC₀₋₂₄) of amisulpride that is less than about 80% ofthe AUC₀₋₂₄ achieved by an immediate release composition having the sametotal daily amount of amisulpride. In various aspects and embodiments,provided are modified release formulations of amisulpride with reduceddrug induced QT prolongation compared to immediate release formulationshaving the same total amount of amisulpride.

As used herein, the terms “AUC”, “Cmax”, “Cmin”, “Tmax”, and “QTinterval prolongation”, unless stated otherwise, when used in thedescriptions herein encompass average, mean, and geometric mean valuesof a population. That is for the sake of conciseness in descriptionphrasing such as “average, mean, and/or geometric mean values” has notbeen included as it is to be understood the disclosures herein aregenerally applicable, mutatis mutandis.

In various aspects and embodiments, provided are modified releaseformulations of non-racemic amisulpride compositions that provide atherapeutic effect at lower amisulpride blood plasma levels (both Cmaxand AUC) than immediate release formulations with substantially the sameD2 dopamine receptor antagonism and 5-HT₇ serotonin receptor antagonism.In various aspects and embodiments, provided are modified releaseformulations of non-racemic amisulpride compositions with reduced druginduced QT prolongation compared to immediate release formulations withsubstantially the same D2 dopamine receptor antagonism and 5-HT₇serotonin receptor antagonism.

The present inventors have discovered that the presence of amisulprideenantiomers in a subject's blood plasma is shorter than the brain D2dopamine receptor occupancy. The present inventors have also discoveredmodified release pharmaceutical formulations of amisulpride that canachieve the same brain D2 dopamine receptor occupancy, but at loweramisulpride blood plasma concentrations (e.g. Cmax, AUC, and both Cmaxand AUC), than immediate release formulations with comparable brain D2dopamine receptor occupancy.

In addition, the present inventors have discovered modified releasepharmaceutical formulations of amisulpride that improve the therapeuticindex of amisulpride. For example, in various aspects and embodiments,the present inventors have discovered modified release pharmaceuticalformulations of amisulpride that provide the substantially similarpharmacodynamics (e.g. efficacy) as immediate release formulations butwith improved pharmacokinetics (e.g. lower Cmax) and/or reduced sideeffects (e.g. reduced QT prolongation).

It has been previously discovered that the R and S amisulpride isomershave different properties. The R isomer is a selective serotoninantagonist. In contrast the S isomer is a highly selective D2 dopamineantagonist. The present inventors provide modified release formulationsusing amisulpride compositions tailored to provide specific antagonismeffects against the D2 dopamine receptors and the 5-HT₇ receptorsindependent of one another. In various aspects and embodiments, theamisulpride compositions used in the modified release formulations havebeen previously shown in immediate release formulations to provide theability to adjust the D2 dopamine and 5-HT₇ receptors antagonismactivity and reduce the adverse effects associated with racemicamisulpride of comparable total dosage amounts. The modified releaseformulations reduce even further the adverse effects associated withracemic amisulpride of comparable total dosage amounts. In short, thepresent inventors have discovered modified release formulations of thesenon-racemic amisulpride compositions that provide substantially the samebenefits in the treatment of bipolar symptoms and depression ascomparable immediate release formulations of non-racemic amisulpridecompositions but with reduced side effects in various embodiments.

In various aspects and embodiments, the non-racemic amisulpridecompositions used in the modified release formulations provide theability to adjust release of the active pharmaceutical ingredients (i.e.enantiomers of amisulpride) such that the D2 dopamine and 5-HT₇receptors antagonism activity (associated, respectively, with Samisulpride and R amisulpride) can be achieved at lower bloodconcentration levels than for comparable immediate release formulationsof comparable total dosage amounts. Thus, in various aspects andembodiments, the modified release formulations reduce the adverseeffects associated with comparable immediate release formulations of thecomparable non-racemic amisulpride compositions, and reduce even furtherthe adverse effects associated with racemic amisulpride of comparabletotal dosage amounts. Adverse effects associated with racemicamisulpride include, but are not limited to, Extrapyramidal Symptoms(EPS), akathisia, sedation, metabolic parameters such as weight gain,glucose and lipids, prolactin related events, sexual dysfunction andmanic depression. Adverse effects associated with both amisulprideenantiomers include, but are not limited to, QT prolongation. In variousaspects and embodiments, the degree of reduction is determined by thedecrease in Cmax.

In various aspects and embodiments, provided are various modifiedrelease formulations, methods and medicaments comprising and/oremploying amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, where the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride, that can provide thediscovered antidepressant activity of (R)-(+)-amisulpride whilemaintaining the mood stabilization activity of (S)-(−)-amisulpride anddecreasing the undesirable side effects associated with immediaterelease formulations of amisulpride. In various aspects and embodiments,modified release formulations decrease the undesirable side effectsassociated with higher levels of dopamine D2 receptor blockadeassociated with (S)-(−)-amisulpride. In various aspects and embodiments,modified release formulations decrease the undesirable amisulpride sideeffect of drug induced QT prolongation.

It has been discovered by the inventors that modified releaseformulations of a fixed-dose combination of amisulpride enantiomers,defined in various embodiments by the contribution of 5-HT₇ occupancyrelative to D2 occupancy, exhibit clinical benefit by allowingphysicians to treat subjects with a dominant 5-HT₇ pharmacodynamicswhile still maintaining a dose-responsive underlying dopamine D2activity for a combined, and in various embodiments improved, clinicalbenefit in depressive disorders, whilst reducing one or more sideeffects associated with comparable immediate release formulations.

In various aspects and embodiments, there are provided modified releasepharmaceutical compositions in a solid oral dosage form comprisingamisulpride in the form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride, and one or more pharmaceutically acceptableexcipients. The one or more pharmaceutically acceptable excipients mayinclude an extended release agent.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itresults in a maximum QT interval prolongation of less than about 0.45milliseconds (ms), less than about 0.30 milliseconds (ms), less thanabout 0.20 milliseconds (ms), less than about 0.10 milliseconds (ms),less than 0.05 milliseconds (ms), or less than 0.02 milliseconds (ms)per 10 mg of amisulpride over the time period of 12 hours afteradministration.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itresults in a maximum QT interval prolongation over the time period of 12hours after administration that is at least about 75%, about 65%, about60%, about 55%, or about 50% less than that of an immediate releasecomposition having the same total daily amount of amisulpride as themodified release pharmaceutical composition.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itresults in a maximum QT interval prolongation over the time period of 12hours after administration that is at least about 75%, about 65%, about60%, about 55%, or about 50% less than that of the immediate releasecomposition described in Table 25 and having the same total daily amountof amisulpride as the modified release pharmaceutical composition.

In various aspects and embodiments, when a modified releasepharmaceutical composition comprising about 200 mg of total amisulprideis administered to a subject population, it results in a maximum QTinterval prolongation over the time period of 12 hours afteradministration that is less than about 10 milliseconds (ms), about 9 ms,about 8 ms, about 7 ms, about 6 ms, or about 5 ms relative to baseline.

In various aspects and embodiments, when a modified releasepharmaceutical composition comprising about 200 mg of total amisulprideis administered to a subject population, it results in QT intervalprolongation at geometric mean Cmax that is less than about 10milliseconds (ms), about 9 ms, about 8 ms, about 7 ms, about 6 ms, orabout 5 ms relative to baseline.

In various aspects and embodiments, the solid oral dosage form, whendissolution tested using in vitro gastrointestinal simulationdissolution test releases (a) less than about 30% of amisulpride afterabout 1 hour, releases more than about 20% and less than about 60% ofamisulpride after about 3 hours, and releases more than about 30% andless than about 100% of amisulpride mixture after about 6 hours; (b)less than about 30% of amisulpride after about 1 hour, releases morethan about 20% and less than about 60% of amisulpride after about 3hours, and releases more than about 30% and less than about 75% ofamisulpride after about 6 hours; (c) less than about 20% of amisulprideafter about 1 hour, releases more than about 20% and less than about 50%of amisulpride after about 3 hours, and releases more than about 30% andless than about 75% of amisulpride after about 6 hours; (d) more thanabout 30% and less than about 50% of amisulpride after about 6 hours;(e) no more than about 30% of amisulpride after about 1 hour, releasesbetween about 30% and about 75% of amisulpride after about 3 hours, andreleases more than about 75% of amisulpride after about 12 hours; or (f)more than about 75% of amisulpride after about 6 hours.

In various aspects and embodiments, the solid oral dosage form, whendissolution tested using the two-stage in vitro dissolution testdescribed in Table 5 in the paddle apparatus described in United StatesPharmacopeia Convention (USP) Apparatus 2 of Chapter 711 Dissolution;USP41-NF36 General Chapter <711> Dissolution releases (a) less thanabout 30% of amisulpride after about 1 hour, releases more than about20% and less than about 60% of amisulpride after about 3 hours, andreleases more than about 30% and less than about 100% of amisulpridemixture after about 6 hours; (b) less than about 30% of amisulprideafter about 1 hour, releases more than about 20% and less than about 60%of amisulpride after about 3 hours, and releases more than about 30% andless than about 75% of amisulpride after about 6 hours; (c) less thanabout 20% of amisulpride after about 1 hour, releases more than about20% and less than about 50% of amisulpride after about 3 hours, andreleases more than about 30% and less than about 75% of amisulprideafter about 6 hours; (d) more than about 30% and less than about 50% ofamisulpride after about 6 hours; (e) no more than about 30% ofamisulpride after about 1 hour, releases between about 30% and about 75%of amisulpride after about 3 hours, and releases more than about 75% ofamisulpride after about 12 hours; or (f) more than about 75% ofamisulpride after about 6 hours.

As used herein, the term “two-stage in vitro gastrointestinal simulationdissolution test” refers to an in vitro test designed to simulate thesolution pH conditions of the stomach (stage 1) and small intestine(stage 2) of a human in a fasted state. The pH of the first stage isbetween about 1.2 to 3.5, and the pH of the second stage is betweenabout 6 to about 7.4. The sample to be tested (e.g. tablet, capsule) isplaced in the liquid medium of the first stage for about an hour (tosimulate residence time in the stomach) prior to the medium being adjustto those of the second stage (to simulate transition to the higher pHenvironment of the small intestine). The dissolution medium is stirredduring the test with a paddle apparatus, substantially in accord witheither that described by the United States Pharmacopeia Convention (USP)Apparatus 2 of Chapter 711 Dissolution; USP41-NF36 General Chapter <711>Dissolution or that described by the paddle method of JapanesePharmacopeia (JP) General test<6.10>, as harmonized with Ph. Eur.<2.9.3> and USP <711>. The paddle apparatus is operated between about 50to about 75 rpm in both stages; and the temperature of the dissolutionmedium in both stages is maintained at about 37° C.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itis effective in minimizing fluctuations between Cmin and Cmax ofamisulpride. In various aspects and embodiments, the modified releasepharmaceutical compositions are effective in minimizing the differencebetween Cmin and Cmax of amisulpride compared to the immediate releasecomposition described in Table 25 and having the same total daily amountof amisulpride as the modified release pharmaceutical compositionwherein the value of Cmin is at about 9 hours after administration.

In various aspects and embodiments, the modified release pharmaceuticalcomposition, when administered to a subject population, is effective inproviding a population mean ratio of Cmax/Cmin of amisulpride that isless than about 2, less than about 1.9, or less than about 1.8, whereinthe value of Cmin is at about 9 hours after administration.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population (i)the area under the curve (AUC) of blood plasma concentration versus timeof amisulpride from administration to Tmax (AUC_(0-Tmax)) is less thanabout 17%, less than about 16%, less than about 15%, less than about14%, less than about 13%, or less than about 12% of the area under thecurve from administration to infinity (AUC_(0-INF)); and (ii) Tmax ofamisulpride is between about 4 and about 6 hours after administration.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population (i)the area under the curve (AUC) of blood plasma concentration versus timeof amisulpride from administration to Tmax (AUC_(0-Tmax)) is less thanabout 19%, less than about 18%, less than about 17%, less than about16%, less than about 15%, less than about 14%, less than about 13%, orless than about 12% of the area under the curve from administration to48 hours (AUC₀₋₄₈); and (ii) Tmax of amisulpride is between about 4 andabout 6 hours after administration.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itprovides a plasma concentration profile substantially the same as theprofile of Lot 4Z in FIG. 22B, Lot 4Z in FIG. 22F, Lot 3Z in FIG. 22C,Lot 3Z in FIG. 22H, Lot 3Z in FIG. 22J, Lot 3Z with subjects in a fedstate in FIG. 22I, Lot 3Z with subjects in a fed state in FIG. 22D, ofLot 5Z in FIG. 22G, or Lot 6Z in FIG. 22K.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itprovides a blood plasma Cmax of amisulpride that is less than about 75%,less than about 65%, less than about 60%, less than about 55%, or lessthan about 50% of the Cmax achieved by the immediate release having thesame total daily amount of amisulpride as the modified releasepharmaceutical composition. In various aspects and embodiments, when themodified release pharmaceutical composition is administered to a subjectpopulation, it provides a blood plasma Cmax of amisulpride that is lessthan about 45%, less than about 40%, less than about 35%, or less thanabout 30% of the Cmax achieved by the immediate release having the sametotal daily amount of amisulpride as the modified release pharmaceuticalcomposition. In various embodiments, an immediate release compositionhas the same total daily amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride as in the modified release pharmaceuticalcomposition.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itprovides a blood plasma Cmax of amisulpride that is less than about 75%,less than about 65%, less than about 60%, less than about 55%, or lessthan about 50% of the Cmax achieved by the immediate release compositiondescribed in Table 25 and having the same total daily amount ofamisulpride as the modified release pharmaceutical composition. Invarious aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itprovides a blood plasma Cmax of amisulpride that is less than about 45%,less than about 40%, less than about 35%, or less than about 30% of theCmax achieved by the immediate release composition described in Table 25and having the same total daily amount of amisulpride as the modifiedrelease pharmaceutical composition. In various embodiments, theimmediate release composition has the same total daily amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride as in the modified releasepharmaceutical composition.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itprovides a blood plasma Cmax of amisulpride that is less than about 75%,less than about 65%, less than about 55%, or less than about 50% of theCmax achieved by an immediate release composition having the same totaldaily amount of amisulpride as the modified release pharmaceuticalcomposition, and when administered to a subject population provides aAUC from 0 to 48 hours after administration (AUC₀₋₄₈) of amisulpridethat is at least about 60%, at least about 70%, or at least about 75% ofthe AUC₀₋₄₈ achieved by an immediate release composition having the sametotal daily amount of amisulpride as the modified release pharmaceuticalcomposition.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itprovides a blood plasma Cmax of amisulpride that is less than about 75%,less than about 65%, less than about 55%, or less than about 50% of theCmax achieved by the immediate release composition described in Table 25and having the same total daily amount of amisulpride as the modifiedrelease pharmaceutical composition, and when administered to a subjectpopulation provides a AUC from 0 to 48 hours after administration(AUC₀₋₄₈) of amisulpride that is at least about 60%, at least about 70%,or at least about 75% of the AUC₀₋₄₈ achieved by the immediate releasecomposition described in Table 25 and having the same total daily amountof amisulpride as the modified release pharmaceutical composition.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itprovides a AUC from 0 to 48 hours after administration (AUC₀₋₄₈) ofamisulpride that is: (a) at least about 40% of the AUC₀₋₄₈ achieved byan immediate release composition having the same total daily amount ofamisulpride as the modified release pharmaceutical composition, (b) atleast about 50% of the AUC₀₋₄₈ achieved by an immediate releasecomposition having the same total daily amount of amisulpride as themodified release pharmaceutical composition (c) at least about 60% ofthe AUC₀₋₄₈ achieved by an immediate release composition having the sametotal daily amount of amisulpride as the modified release pharmaceuticalcomposition, (d) at least about 70% of the AUC₀₋₄₈ achieved by animmediate release composition having the same total daily amount ofamisulpride as the modified release pharmaceutical composition, (e) atleast about 75% of the AUC₀₋₄₈ achieved by an immediate releasecomposition having the same total daily amount of amisulpride as themodified release pharmaceutical composition, and/or (f) at least about80% of the AUC₀₋₄₈ achieved by an immediate release composition havingthe same total daily amount of amisulpride.

In various aspects and embodiments, when the modified releasepharmaceutical composition is administered to a subject population, itprovides a AUC from 0 to 48 hours after administration (AUC₀₋₄₈) ofamisulpride that is: (a) at least about 40% of the AUC₀₋₄₈ achieved bythe immediate release composition described in Table 25 and having thesame total daily amount of amisulpride as the modified releasepharmaceutical composition, (b) at least about 50% of the AUC₀₋₄₈achieved by the immediate release composition described in Table 25 andhaving the same total daily amount of amisulpride as the modifiedrelease pharmaceutical composition, (c) at least about 60% of theAUC₀₋₄₈ achieved by the immediate release composition described in Table25 and having the same total daily amount of amisulpride as the modifiedrelease pharmaceutical composition, (d) at least about 70% of theAUC₀₋₄₈ achieved by the immediate release composition described in Table25 and having the same total daily amount of amisulpride as the modifiedrelease pharmaceutical composition, (e) at least about 75% of theAUC₀₋₄₈ achieved by the immediate release composition described in Table25 and having the same total daily amount of amisulpride as the modifiedrelease pharmaceutical composition, and/or (f) at least about 80% of theAUC₀₋₄₈ achieved by the immediate release composition described in Table25 and having the same total daily amount of amisulpride.

In various aspects and embodiments, the modified release pharmaceuticalcompositions, and methods of treatment refer to a subject population andprovision of certain effects thereto, and/or parameters that are thoseof a subject population (e.g. a subject population average). It is to beunderstood that when such reference is made to a subject population orin a subject population the effect is that determined from the overalleffect in the subject population, e.g. the subject population average ofa measured parameter, the subject population geometric mean of ameasured parameter, etc. It is not required that any one subject exhibitthe effect as specified, nor is it required that every subject exhibitthe effect as specified; rather it is the value of the effect (e.g. QTinterval, Cmax, Cmin, Tmax, AUC, D2 occupancy, etc.) for the population.As described herein, the value for an effect when used in thedescriptions herein encompass average, mean, and geometric mean valuesof a population. That is for the sake of conciseness in descriptionphrasing such as “average, mean, and/or geometric mean values” has notbeen included as it is to be understood the disclosures herein aregenerally applicable, mutatis mutandis.

In various aspects and embodiments, the effects of a modified releasepharmaceutical compositions, and methods of treatment using the same,are compared to an immediate release formulation and/or a comparableimmediate release formulation having the same total daily amount ofamisulpride. It is to be understood that such comparable immediaterelease formulations are those that are substantially similar informulation composition to the corresponding modified releaseformulations except where the extended release agent in the modifiedrelease formulation has been replaced by substantially the same filleras used in the modified release formulation, with the understanding thatminor variations in excipients such as, e.g., lubricants, glidants andbinders, necessary for dosage form formation are acceptable. Forexample, in various embodiments, modified release formulations arecompared to an immediate release formulation substantially similar tothat of Lot 1D, and the comparable immediate release formulation is thatof Lot 1D; and in various embodiments, modified release formulations arecompared to an immediate release formulation substantially similar tothat of Lot 1Z, and the comparable immediate release formulation is thatof Lot 1Z.

These and other objects, features, and advantages of the inventions willbecome apparent from the following detailed description of the variousaspects and embodiments of the inventions taken in conjunction with theaccompanying tables and drawings.

All published documents cited herein are hereby incorporated herein byreference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D present various in vitro dissolution profiles for variousmodified release pharmaceutical matrix tablet formulations of 85:15(R:S-amisulpride); where FIG. 1A presents data for the formulations ofTable 1; FIG. 1B presents data for the formulations of Table 2; FIG. 1Cpresents data for the formulations of Table 3A; FIG. 1 D presents datafor the formulations of Tables 24A and 24B, and FIG. 1E presents datafor the formulations of Table 3C.

FIGS. 2A-2C present various scanning electron microscope (SEM) images ofthe particulates of Table 11; where FIG. 2A is a 50× image of the IRparticles, FIG. 2B is a 50× image of Lot SC30, and FIG. 2C is a 50×image of Lot SC60.

FIG. 3A presents various in vitro dissolution profiles for an immediaterelease (IR) formulation and various modified release pharmaceuticalmultiparticulate capsule (MUPS) formulations of Table 10.

FIG. 3B presents various in vitro dissolution profiles for an immediaterelease (IR) formulation and various modified release pharmaceuticalmultiparticulate capsule (MUPS) formulations of Table 11.

FIG. 4A presents various in vitro dissolution profiles for variousmodified release pharmaceutical multiparticulate capsule (MUPS)formulations of 85:15 (R:S-amisulpride) of Table 16A.

FIG. 4B presents various in vitro dissolution profiles for variousmodified release pharmaceutical multiparticulate capsule (MUPS)formulations of 85:15 (R:S-amisulpride) of Table 16B.

FIGS. 5A-5C present various analytical in vitro data for the inhibitionof radioligand binding activity by racemic amisulpride, (R)-amisulpride,and (S)-amisulpride, and various mixtures of (R)-amisulpride and(S)-amisulpride; where FIG. 5A presents data on the % inhibition ofdopamine D2 receptor binding; FIG. 5B presents data on the % inhibitionof serotonin 5-HT7 receptor binding; and FIG. 5C presents data onrelative receptor affinity (5-HT7: D2) for various mixtures of(R)-amisulpride and (S)-amisulpride.

FIG. 6 presents analytical data on the in vivo effects of(R)-amisulpride in a Rat Forced Swim Test, compared to vehicle andimipramine.

FIGS. 7A and 7B present analytical data on the in vivo effects of(R)-amisulpride on suppression of REM sleep time in rats; FIG. 7Apresents data comparing vehicle to 10 mg/kg and 100 mg/kg of(R)-amisulpride, and FIG. 7B presents data comparing vehicle to 10mg/kg, 30 mg/kg and 100 mg/kg of (R)-amisulpride.

FIGS. 7C, 7D, and 7E present analytical data on the in vivo effects of85:15 ratio (R:S-amisulpride) and racemic amisulpride (50:50R:S-amisulpride) on suppression of REM sleep time in rats. FIG. 7Cpresents data comparing vehicle to 30 mg/kg and 100 mg/kg of 85:15 ratio(R:S-amisulpride) and racemic amisulpride in REM sleep time (min). FIG.7D presents data comparing vehicle to 30 mg/kg and 100 mg/kg of 85:15ratio (R:S-amisulpride) and racemic amisulpride in NREM sleep time(min). FIG. 7E presents data comparing vehicle to 30 mg/kg and 100 mg/kgof 85:15 ratio (R:S-amisulpride) and racemic amisulpride in WAKE time(min).

FIG. 8 presents analytical data from human clinical studies on theeffects of (S)-amisulpride binding to dopamine D2 receptors in the brainof human volunteers using PET imaging.

FIG. 9 presents analytical data from human clinical studies on theeffects of (R)-amisulpride in suppressing REM sleep in human volunteersusing PSG to record sleep stages.

FIGS. 10A, 10B and 10C present analytical data on the effects ofmixtures of amisulpride; where FIG. 10A presents data from humanclinical studies on the binding to dopamine D2 receptors of an 85:15ratio by weight percentage (w/w %) of (R)-amisulpride to(S)-amisulpride, FIG. 10B illustrates data on a racemic (50:50 ratio byweight percentage mixture of (R)-amisulpride to (S)-amisulpride), andFIG. 10C illustrates the substantial overlap of the 5-HT₇ effect with30% to 50% D2 receptor occupancy that may be achieved withadministration of an 85:15 ratio by weight percentage (w/w %) mixture of(R)-amisulpride to (S)-amisulpride. In FIG. 10B the mg designationswithin the field of the graph indicate the amount of the indicatedenantiomer in the racemic mixture. In FIG. 10C the grey shaded circlesare the data for (S)-amisulpride from FIG. 10B plotted on the FIG. 10Cx-axis as the total mg amount required to deliver the indicated amountof (S)-amisulpride in the (R)-amisulpride:(S)-amisulpride (85:15)mixture, the dark shaded circles are the data for (R)-amisulpride fromFIG. 10B plotted on the FIG. 10C x-axis as the total mg amount requiredto deliver the indicated amount of (R)-amisulpride in the(R)-amisulpride:(S)-amisulpride (85:15) mixture, and the white diamondsymbols are data for the administration of an 85:15 ratio by weightpercentage (w/w %) mixture of (R)-amisulpride to (S)-amisulpride.

FIGS. 11A-11C present various analytical data and images for Form Acrystals of (R)-amisulpride, where FIG. 11A presents a DSC thermogram;FIG. 11B a XRPD pattern; and FIG. 11C a micrograph image.

FIGS. 12A-12D present various analytical data and images for Form A′crystals of (S)-amisulpride, where FIG. 12A presents a DSC thermogram;FIG. 12B a XRPD pattern; FIG. 12C a micrograph image; and FIG. 12D a DVSwater sorption isotherm.

FIG. 13 is an NMR spectrum of anR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A′.

FIG. 14 is an NMR spectrum of anS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A′.

FIG. 15A is an NMR spectrum of anR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A, and FIG. 15B illustrates the number sequenceused for the assignment of peaks in FIG. 15A.

FIG. 16A is an ¹³C NMR spectrum of anR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A, and FIG. 16B illustrates the number schemeused for the assignment of peaks in FIG. 16A.

FIG. 17A is an NMR spectrum of anS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A′, and FIG. 17B illustrates the numbersequence used for the assignment of peaks in FIG. 17A.

FIG. 18A is an ¹³C NMR spectrum of anS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A′, and FIG. 18B illustrates the number schemeused for the assignment of peaks in FIG. 18A.

FIGS. 19A, 19B, and 19C present analytical data on the effects ofmixtures of amisulpride.

FIG. 19A presents data from human clinical studies on the effects of(R)-amisulpride (dark circles) on 5-HT₇ shown by suppression of REMsleep from Example 5, where the x-axis in the top graph is 50:50 racemicamisulpride, and the x-axis in the bottom graph is 85:15 ratio by weightpercentage (w/w %) of R:S-amisulpride.

FIG. 19B presents data from human clinical studies on the binding todopamine D2 receptors of (S)-amisulpride and an 85:15 ratio by weightpercentage (w/w %) of (R)-amisulpride to (S)-amisulpride. The x-axis inthe top graph is 50:50 racemic amisulpride. The top graph shows theamount of (S)-amisulpride (grey circles) has on D2 occupancy based ondata from Example 4. The x-axis in the bottom graph is 85:15 ratio of(R)-amisulpride to (S)-amisulpride, showing the amount of(S)-amisulpride (grey circles) and 85:15 ratio (white diamonds) have onD2 occupancy based on data from Example 4 and Example 6, respectively.

FIG. 19C illustrates the substantial overlap of the 5-HT₇ effect with30% to 50% D2 receptor occupancy that may be achieved withadministration of an 85:15 ratio by weight percentage (w/w %) mixture of(R)-amisulpride to (S)-amisulpride. The x-axis in the top graph is thetotal amount of racemic amisulpride. The mg designations indicate theamount of the indicated enantiomer in the racemic mixture. The greyshaded circles are the data for (S)-amisulpride from Example 4, showingthe effect of (S)-amisulpride has on D2 occupancy. The dark circles arethe data for (R)-amisulpride from Example 5, showing the effect of(R)-amisulpride has on 5-HT₇. The x-axis in the bottom graph is thetotal amount of 85:15 ratio R:S amisulpride. The mg designationsindicate the amount of the indicted enantiomer in the 85:15 ratiomixture. The grey shaded circles are the data for (S)-amisulpride fromExample 4, showing the effect of (S)-amisulpride has on D2 occupancy.The dark circles are the data for (R)-amisulpride from Example 5,showing the effect of (R)-amisulpride has on 5-HT₇. The white diamondsare data for the 85:15 ratio R:S amisulpride from Example 6 (D2occupancy).

FIGS. 20A and 20B present, respectively, the geometric mean of Cmax andAUC for the subjects of Example 7A, the error bars represent the 95%confidence intervals.

FIGS. 20C and 20D present, respectively, the geometric mean of Cmax andAUC for the subjects of Example 7A Part 1 (open squares) and Part 2(filled squares), the error bars represent the 95% confidence intervals.Two squares are shown for Lot 3Z in FIGS. 20C and 20D, one squarepresenting data for Lot 3Z administered in the fed state, and the otherfor Lot 3Z administered in a fasted state, see Table 27B.

FIGS. 21A and 21B present, respectively, average Cmax and AUC for thesubjects of the study of Example 7A, Part 1, the error bars representthe ±95% confidence intervals. The values for Cmax and AUC have beennormalized for each subject to the Cmax and AUC value of that subjectwhen administered the IR tablet, i.e. a tablet having a compositionsubstantially similar to that of Lot 1Z.

FIG. 21C presents geometric mean Tmax data for the subjects of the studyof Example 7A, Part 1, the error bars represent the ±95% confidenceintervals.

FIGS. 21D and 21E present, respectively, geometric mean Cmax and AUC forthe subjects of the study of Example 7A, Part 1 (open squares) and Part2 (filled squares), the error bars represent the ±95% confidenceintervals. In FIGS. 21D and 21E the values for Cmax and AUC have beennormalized for each subject to the Cmax and AUC value of that subjectwhen administered the IR tablet, i.e. a tablet having a compositionsubstantially similar to that of Lot 1Z. Two squares are shown for Lot3Z in FIGS. 21D and 21E, one square presenting data for Lot 3Zadministered in the fed state, and the other for Lot 3Z administered ina fasted state, see Table 28B.

FIG. 21F presents geometric mean Tmax data for the subjects of the studyof Example 7A, Part 1 (open squares) and Part 2 (filled squares), theerror bars represent the ±95% confidence intervals. Two squares areshown for Lot 3Z in FIG. 21F, the upper square presenting data for Lot3Z administered in the fed state, and the lower square Lot 3Zadministered in a fasted state.

FIGS. 22A-FIG. 22K present data on the average blood plasmaconcentration over time from the human clinical studies of Example 7Afor various modified releases pharmaceutical compositions compared tothe immediate release formulation (Lot 1Z) used in the study.

FIGS. 22A-22D present data for subjects who were successfullyadministered all of the formulations of Part 1 of Example 7A (n=12) thatis for subjects who each administered Lot 1Z, Lot 2Z, Lot 4Z, Lot 3Z,and Lot 3Z fed state. FIG. 22A presents data on Lot 2Z compared to Lot1Z, FIG. 22B presents data on Lot 4Z compared to Lot 1Z in Example 7APart 1, FIG. 22C presents data on Lot 3Z compared to Lot 1Z in Example7A Part 1, and FIG. 22D presents data on Lot 3Z when a subject is in afed state (taken within 30 minutes after a meal), compared to Lot 1Z inExample 7A Part 1.

FIGS. 22E-22K present data where all subjects were included (forexample, for Lot 1Z (IR) n=17, for Lot 2Z (10%) n=15, Lot 4Z (15%) n=14,Lot 5Z (20%) n=18, Lot 3Z (25%) n=16, Lot 3Z (25% fed state) n=12, andfor Lot 6Z (40%) n=17.

FIG. 22E presents data on Lot 2Z compared to Lot 1Z for all subjectsadministered Lot 2Z or 1Z in Example 7A Part 1.

FIG. 22F presents data on Lot 4Z compared to Lot 1Z for all subjectsadministered Lot 4Z or 1Z in Example 7A Part 1.

FIG. 22G presents data on Lot 5Z compared to Lot 1Z in Example 7A Part 2for all subjects administered Lot 5Z or 1Z in Example 7A Part 2.

FIG. 22H presents data on Lot 3Z compared to Lot 1Z for all subjectsadministered Lot 3Z or 1Z in Example 7A Part 1.

FIG. 22I presents data on Lot 3Z when a subject is in a fed state (takenwithin 30 minutes after a meal) compared to Lot 1Z for all subjectsadministered Lot 3Z in a fed state or 1Z in Example 7A Part 1.

FIG. 22J presents data on Lot 3Z compared to Lot 1Z for all subjectsadministered Lot 3Z or 1Z in Example 7A Part 2.

FIG. 22K presents data on Lot 6Z compared to Lot 1Z for all subjectsadministered Lot 6Z or 1Z in Example 7A Part 2.

FIG. 23 compares the difference (IR-MR) between AQTcF max for IR andmodified release (MR) formulations for the subjects of Example 7A Parts1 and 2, the error bars represent the ±90% confidence intervals.

FIGS. 24A-24D present data on D2 receptor occupancy for the subjects ofExample 7B; FIGS. 24A and 24B present data on percentage D2 receptoroccupancy for subjects 27.5±1 hour following the first dose, and FIGS.24 C and 24D present data on percentage D2 receptor occupancy forsubjects 27.5±1 hour following the seventh dose. The error barsrepresent the ±90% confidence intervals.

FIG. 25 compares the difference (MR-IR) between D2 receptor occupancymeasured for IR and modified release (MR) formulations for the subjectsof Example 7B, the error bars represent the ±90% confidence intervals.

FIG. 26A presents normalized Cmax data from Example 7A (Part 1, Part 2,and Parts 1 & 2 combined) and Example 7B. The Cmax for subjects ofExample 7A has been normalized for each subject to the Cmax value ofthat subject when administered the IR tablet (i.e. a tablet having acomposition substantially similar to that of Lot 1Z). The normalizedCmax data for Example 7B is the geometric mean Cmax of subjectsadministered a modified release (MR) composition substantially similarto that of Lot 3Z normalized by the geometric mean Cmax of the subjectsadministered the IR tablet having a composition substantially similar tothat of Lot 1Z. The error bars represent the ±90% confidence intervals.

FIG. 26B presents normalized Cmax data for Example 7B as measured on Day1, Day 3 and Day 7, where the geometric mean Cmax of subjectsadministered a modified release (MR) composition substantially similarto that of Lot 3Z is normalized by the geometric mean Cmax of thesubjects administered the IR tablet having a composition substantiallysimilar to that of Lot 1Z. The error bars represent the ±90% confidenceintervals.

FIG. 27A presents normalized AUC data from Example 7A (Part 1, Part 2,and Parts 1 & 2 combined) and Example 7B (Days 1 & 7 combined).AUC_(0-INF) values are used for the subjects of Example 7A and AUC₀₋₂₄are used for the subjects of Example 7B. The AUC for subjects of Example7A has been normalized for each subject to the AUC value of that subjectwhen administered the IR tablet (i.e. a tablet having a compositionsubstantially similar to that of Lot 1Z). The normalized AUC data forExample 7B is the geometric mean AUC of subjects administered a modifiedrelease (MR) composition substantially similar to that of Lot 3Znormalized by the geometric mean AUC of the subjects in Example 7Badministered the IR tablet having a composition substantially similar tothat of Lot 1Z. The error bars represent the ±90% confidence intervals.

FIG. 27B presents normalized AUC₀₋₂₄ data for Example 7B as measured onDay 1 and Day 7, where the geometric mean AUC₀₋₂₄ of subjectsadministered a modified release (MR) composition substantially similarto that of Lot 3Z is normalized by the geometric mean AUC₀₋₂₄ of thesubjects administered the IR tablet having a composition substantiallysimilar to that of Lot 1Z. The error bars represent the ±90% confidenceintervals.

FIG. 28A presents data for a single subject comparing the amisulprideblood plasma concentration as a function of time (white circles) to D2receptor occupancy (white diamonds) as a function of time following asingle day dosing.

FIG. 28B compares observed D2 receptor occupancy as measured in Example7B (white circles where total daily does is indicated) to predictedaccumulation (solid lines, dosage for prediction is indicated).

FIG. 29 presents a calculated XRPD based on single crystal structuredetermination for (R)-amisulpride Form A.

FIG. 30 presents a calculated XRPD based on single crystal structuredetermination for (S)-amisulpride Form A′.

DETAILED DESCRIPTION

Reference in the specification to “one embodiment,” “an embodiment,”“one aspect,” or “an aspect” means that a particular, feature, structureor characteristic described in connection with the embodiment or aspectis included in at least one embodiment or aspect of the teachings.

As used herein, the recitation of “amisulpride,” unless expresslyfurther limited, refers to amisulpride in any enantiomeric ratioincluding, equal mixtures of R-amisulpride and S-amisulpride, pureR-amisulpride, pure S-amisulpride, and unequal mixtures of R-amisulprideand S-amisulpride. In addition, as used herein, the recitation of“amisulpride,” unless expressly further limited, includespharmaceutically acceptable salts of amisulpride. As used herein, theterm “racemic amisulpride” refers to a 50:50 mixture by weight of(R)-amisulpride and (S)-amisulpride.

As used herein the term “extended release agent” means an excipient thatlowers the rate of gastric dissolution of amisulpride in a solid oraldosage form formulation such that the amisulpride is released over anextended time. Extended release agents include, but are not limited to,polymer coatings, polymer matrix systems, enzyme-activated systems,systems that respond to changes in physical conditions, such as, e.g.,pH, etc., agents that are hydrophilic, agents that are hydrophobic, etc.

As used herein, the phrase “QT interval” refers to the heart ratecorrected QT interval as determined using Fridericia's formulaQTcF=QT/∛RR, that is herein “QT interval” refers to QTcF. As used hereinthe phrase “QT interval prolongation” refers to the change in the QTcFinterval relative to the baseline QTcF interval. i.e., (ΔQTcF).

As used herein, the term “fed state” refers to the metabolic stateshortly after ingestion of a meal. Measurements of a fed statepharmacokinetic parameters, such as for example, Cmax, Tmax, AUC can beconducted as follows. Following an overnight fast of at least 10 hours,subjects consume a meal comprising 150, 250, and 400-600 calories fromprotein, carbohydrate, and fat, respectively. This meal should beconsumed about 30 minutes prior to administration of the drug productand subjects should eat this meal in 30 minutes or less. No food shouldbe allowed for at least 4 hours post-dose. Water can be allowed asdesired except for one hour before and after drug productadministration.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthaleneslfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Although pharmaceutically acceptable counter ions will bepreferred for preparing pharmaceutical formulations, other anions arequite acceptable as synthetic intermediates.

As used herein, the term “subject,” to which administration iscontemplated includes, but is not limited to, humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., infant, child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesusmonkeys); and mammals used for the testing of pharmaceuticals.

Unless otherwise specified, the word “includes” (or any variationthereon, e.g., “include”, “including”, etc.) is intended to beopen-ended. For example, “A includes 1, 2 and 3” means that A includesbut is not limited to 1, 2 and 3.

As used herein, the terms “treatment,” “treat,” and “treating” refer toalleviating, inhibiting, and/or reducing one or more signs or symptomsof a disease, condition, or disorder. In various embodiments, treatmentmay be administered after one or more symptoms have developed. Treatmentmay also be continued after symptoms have resolved, for example toprevent or delay their recurrence.

As used herein, the term “therapeutic index” is a comparison of theamount of a drug that causes the therapeutic effect to the amount thatcauses one or more undesired effects, such as adverse events and/or sideeffects.

As used herein, the phrase “on a free base basis” indicates that theamount of amisulpride (R and S-amisulpride) is measured based on themolecular weight of amisulpride free base. Unless specified otherwise,the weight amount described herein for amisulpride (e.g., racemic, R, S,or unequal mixtures of R and S amisulpride) refers to the free base. Forexample, in a mixture of 85:15 ratio of R:S-amisulpride by weight, theamount of amisulpride is measured based on the molecular weight of R andS-amisulpride free base unless stated otherwise.

The compounds disclosed herein can include isotopes. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. In someembodiments, one or more atoms of the compounds can be replaced orsubstituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, one or more hydrogen atoms in a compoundof the present disclosure can be replaced or substituted by deuterium.

As used herein, and unless otherwise specified, the term “about”, whenused in connection with a numeric value or range of values may vary by5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or0.1% of the recited value or range of values. In some embodiments, thenumeric value or range of values vary by 5%.

As used herein, and unless otherwise specified, the term“therapeutically effective” when used in connection with thepharmaceutical compositions of the present inventions means a biologicalor medical response which is sought or desired, for example, by aresearcher or physician, such as improved treatment, healing, preventionor elimination of a disease, syndrome, condition, complaint, disorder orside-effects or also the reduction in the advance of a disease,complaint or disorder. The term “therapeutically effective amount” whenused in connection with the pharmaceutical compositions of the presentinventions means an amount of a medicament or of an activepharmaceutical ingredient that is therapeutically effective. Forexample, in various aspects and embodiments, a therapeutically effectiveamount for the treatment of a depressive disorder (e.g. depressiveepisodes associated with a bipolar disorder) is an amount that providesan average occupancy of dopamine D2 receptors between about 20% andabout 60% (e.g. as measured and described herein). In various aspectsand embodiments, a therapeutically effective amount for the treatment ofa depressive disorder (e.g. depressive episodes associated with abipolar disorder) is an amount that reduces depressive symptoms asmeasured by the reduction in total score on a questionnaire employingthe Montgomery-Åsberg Depression Rating Scale (MADRS) and/or theself-rating version MADRS-S.

The term “therapeutically effective blood plasma concentration” whenused in connection with the pharmaceutical compositions of the presentinventions means an active pharmaceutical ingredient blood plasmaconcentration that is therapeutically effective.

Other abbreviations not explicitly described herein have their normalmeanings in the art.

It is to be understood that AUC and AUC_(0-INF) are determined as isnormal in the art. Specifically, AUC_(0-INF) was determined from theformula: AUC_(0-INF)=AUC_(0-last)+C_(last)/λz; where “last” is the lasttime point for which the blood plasma concentration (C) was measured,and where λz=a first-order rate constant associated with the terminal(log-linear) portion of the blood plasma concentration curve. The valuefor λz was determined by linear regression analysis of the time vs. logof the blood plasma concentration data.

The present disclosures relate to modified release formulations ofpharmaceutical compositions comprising unequal mixtures of amisulprideenantiomers, medicaments for the treatment of a disorder comprisingmodified release formulations of unequal mixtures of amisulprideenantiomers, methods of treating a disorder in a subject with modifiedrelease formulations of pharmaceutical compositions comprising unequalmixtures of amisulpride enantiomers, and methods of inhibiting dopamineD2 activity and serotonin 5-HT7 activity in a subject with modifiedrelease formulations comprising unequal mixtures of amisulprideenantiomers.

In various aspects, the disorder which the medicaments and methods treatcomprise one or more of a: psychiatric disorder; mood disorder;depressive disorder; as an adjunctive treatment of major depressivedisorder; bipolar disorder; bipolar depression; schizophrenia; negativesymptoms of schizophrenia; treatment resistant depression (TRD);schizoaffective disorder; anxiety disorder; obsessive-compulsivedisorder; behavior disturbances associated with a neurocognitivedisorder; conduct disorder; neurological disorder; medication-inducedmovement disorder; and motor disorder.

Amisulpride has a single asymmetric center and as a result exists in twoenantiomeric forms:R-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(also referred to as:(R)-(+)-4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,and under the IUPAC name as4-amino-5-(ethanesulfonyl)-N-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}-2-methoxybenzamide),abbreviated herein as (R)-(+)-amisulpride or (R)-amisulpride; andS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(also referred to as:(S)-(−)-4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,and under the IUPAC name as4-amino-5-(ethanesulfonyl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-methoxybenzamide),abbreviated herein as (S)-(−)-amisulpride or (S)-amisulpride. These twoenantiomeric forms have the following chemical structures:

Dopamine D₂-related side effects are well-known from clinicalexperience. It has been observed that the incidence of extrapyramidalside effects increases when occupancy exceeds the 80% threshold andstudies have shown that extrapyramidal side effects occur even at about70-75% occupancy (G. Grunder, et al., Nature, 8, 198-202, (2009);Nyberg, et al., Am. J. Psychiatry, 156, 873-875 (1999); Farde, et al.Arch. Gen. Psychiatry, 49, 538-544 (1992)). However, it is believed thatvery high D2/3 receptor occupancy is not only associated with butgenerally required for effectiveness against the positive symptoms ofschizophrenia and that the antipsychotic effects of dopamine receptorantagonists occur within a therapeutic window between 60 and 80%striatal D2/3 receptor occupancy. (G. Grunder, et al., Nature, 8,198-202, (2009)).

Dopamine D₂-related side effects are also known from clinical experiencewith racemic amisulpride and include Extrapyramidal Symptoms (EPS),Tardive Dyskinesia (TD), and Akathisia. (C. Coulouvrat et al.,International Clinical Psychopharmacology, Vol 14, No. 4, 209-218(1999)). It has been determined that in general D₂ occupancy greaterthan about 67% results in side-effects that limit the ability of theunderlying 5-HT₇ pharmacodynamics to contribute to clinical benefit as afunction of dose. (Farde, et al. Arch. Gen. Psychiatry, 49, 538-544(1992). The impact of D₂ occupancy is associated with age with EPSevents being noted in older patients with Alzheimer's at occupancies ofabout 60%; clinically meaningful responses were seen at occupancies of43%. (Reeves et al., Brain, 140, 1117-1127). Similar results were alsoobtained with older patients in general. (Uchida et al., The American J.of Geriatic Pyschiatry, 22 (1) 1007-1016).

Selective serotonin 5-HT7 antagonists are known to modulate rapid eyemovement (REM) sleep in rodents and humans (Bonaventure et al, 2012). Ingeneral, REM suppression is understood to be a translational biomarkerof serotonergic antidepressant-like activity appropriate for selectinghuman doses. The 5-HT7 receptor has been shown, through variouspharmacological tools (receptor-specific agonists and antagonists) andthrough the use of knockout models, to be involved in the centralregulation of sleep and circadian rhythms, mood, and cognition. Thesesame three domains are often critically impaired in mood disorders suchas major depressive disorder and bipolar disorder, as well as inpsychotic disorders.

The present inventors have demonstrated that various modified releaseformulations having amisulpride in the form of an unequal mixture of the(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, can provide substantially similar or improvedefficacy (e.g. in the treatment of bipolar disorder, depressive episodesassociated with bipolar disorder, and/or depression) compared tocomparable immediate release formulations whilst reducing undesired sideeffects, such as, for example, drug induced QT prolongation and/or thoseassociated with higher levels of dopamine D₂ receptor blockade.

The beating of the heart is due to precisely controlled regularly spacedwaves of myocardial excitation and contraction, arising from ion-baseddepolarization and repolarization. The electrical currents duringdepolarization and repolarization can be measured by leads placed on thebody in specific locations (the electrocardiogram) to measure theelectrical waves. The P-wave in an electrocardiogram represents a waveof depolarization in the atrium. When the entire atria becomesdepolarized, the wave returns to zero, and after 0.1 seconds theventricle is entirely depolarized resulting in the QRS complex seen inthe electrocardiogram (ECG). The three peaks of the QRS complex are dueto the way the current spreads in the ventricles. The QRS complex isfollowed by the T-wave, or repolarization of the ventricle. The QTinterval is measured from the beginning of the QRS complex to the end ofthe T wave on the standard ECG. The QT interval represents the durationtill the completion of the repolarization, phase of the cardiac myocyte(or the depolarization and repolarization of the ventricle).Prolongation of the QT interval, can result in ventricular arrhythmias,and sudden death.

Amisulpride is a drug well known to induce QT interval prolongation,evidencing a substantially linear increase of prolongation with plasmaconcentration. (See, Taubel et al., Br. J. Clin. Pharmacology, 83, pp.339-348 (2017)). The dangers associated with drug induced QTprolongation are also well known: “Although a QT interval of at least500 milliseconds generally has been shown to correlate with a higherrisk of Torsades de Pointes, there is no established threshold belowwhich prolongation of the QT interval is considered free ofproarrhythmic risk” (see Al-Khatib et al., JAMA, 289 (16), pp 2120-2127(2003)). Therefore, there is need for better amisulpride formulationswith reduced side effects such as QT interval prolongation.

In various aspects and embodiments, provided are various modifiedrelease formulations, methods and medicaments comprising an unequalmixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,that can provide the antidepressant activity of (R)-(+)-amisulpridewhile maintaining the mood stabilization activity of (S)-(−)-amisulprideand decreasing the undesirable side effects associated with comparableimmediate release formulations. In various aspects and embodiments, themodified release formulations decrease the undesirable side effectsassociated with higher levels of dopamine D₂ receptor blockadeassociated with (S)-(−)-amisulpride. In various aspects and embodiments,the modified release formulations decrease the undesirable side effectof drug induced QT prolongation associated with both enantiomers ofamisulpride.

In various aspects and embodiments, the modified release compositionsare provided in a solid oral dosage form comprising amisulpride in theform of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-ami sulpride; and one or more pharmaceutically acceptableexcipients. In various embodiments, the one or more pharmaceuticallyacceptable excipients include one or more extended release agents.

In various aspects and embodiments, when the modified releasecomposition is administered to a subject population, it provides overthe time period of 12 hours after administration a maximum QT intervalprolongation of: (a) less than about 0.45 milliseconds (ms) per 10 mg ofamisulpride; (b) less than about 0.30 milliseconds (ms) per 10 mg ofamisulpride; (c) less than about 0.20 milliseconds (ms) per 10 mg ofamisulpride; (d) less than about 0.15 milliseconds (ms) per 10 mg ofamisulpride; (e) less than about 0.10 milliseconds (ms) per 10 mg ofamisulpride; (f) less than about 0.05 milliseconds (ms) per 10 mg ofamisulpride; or (g) less than about 0.02 milliseconds (ms) per 10 mg ofamisulpride.

In various aspects and embodiments, the modified release compositionscan reduce the population average maximum QT interval prolongation overthe time period of about 12 hours after administration to a subjectpopulation relative to that for a comparable immediate releaseformulation.

For example, in various embodiments, the modified release compositionswhen administered to a subject population result in a population averagemaximum QT interval prolongation over the time period of about 12 hoursafter administration that is: (a) at least about 75%, at least about70%, at least about 65%, at least about 60%, at least about 55%, or atleast about 50% less than that of the immediate release compositiondescribed in Table 25 and having the same total daily amount ofamisulpride as the modified release composition.

A variety of methods are known to the medical art to measure a person'sQT interval. The QT interval represents the duration of ventriculardepolarization and subsequent repolarization. Herein, the followingmethod is used to determine “QT interval prolongation.”Electrocardiograms (ECGs) are recorded using a digital 12-lead HolterECG device (for example, such as a Mortara H12+, Mortara Instruments,Milwaukee, Wis.) at a sampling rate of 1000 samples/second (1000 HZ).The Holter ECG recordings are started at least about 1 hour beforedosing with the active pharmaceutical ingredient (API) being evaluatedand continued for at least 12 hours and preferably until 24 hours afterdosing. Ten ECG replicate measurements are made at least at thefollowing time points and within 7 minutes of the time point: 45, 30,and 15 minutes before dosing (baseline) and at 1, 2, 3, 4, 6, 8, 10, and12 hours (and optionally 24 hours) after dosing. As heart rate canaffect the measurements, subjects are in a supine position duringmeasurement.

The determination of QT interval prolongation herein for an API shouldexclude ECGs that exhibit morphological abnormalities, such as of the Pwave, QRS complex, ST segment, T wave, U wave, rhythm and axis.

The ECGs are to be read and interpreted by a qualified cardiologist. TheQT interval is measured from the initiation of the QRS complex (firstdeflection of the QRS complex) to the point of where the T wave returnsto the isoelectric baseline. The end of the T wave is identified as theintersection of the descending part of the T wave (positive T wave) withthe isoelectric line. If a U wave interrupts the T wave before itreturns to baseline, the QT interval is measured as the nadir between Tand U waves. If it is not clear whether the second deflection towardsthe descending part of the T wave is a part of the T wave or a U wave,then it is included in the QT interval. (see, e.g., Panicker G K, et al.“Intra- and interreader variability in QT interval measurement bytangent and threshold methods in a central electrocardiogramlaboratory.” J Electrocardiol. 2009; 42:348-52).

The first five beats in a single lead with at least three consecutivecomplexes during normal rhythm, is used to measure the QT and precedingRR intervals. The PR interval and QRS duration measurements are made inthe appropriate leads. Heart rate (HR) is calculated from the mean RRvalue. The QT interval has an inverse relationship with heart rate andshortens with increasing heart rate. As QT interval varies with changein heart rate, a heart rate correction formulae is used to transform themeasure QT interval into a heart rate independent corrected value knownas the QTc interval. The QTc value is intended to represent the QTinterval at a standardized heart rate of 60 bpm.

The QT interval values are corrected for the effect of heart rate usingthe Fridericia's formula QTcF=QT/∛RR. QTcF of a given time point iscalculated from the mean QT value and the mean RR interval value at thattime point. QT interval prolongation is determined as the mean changefrom baseline values using the calculated QTcF values. Accordingly the“QT interval prolongation” at a time point is the mean QTcF change frombaseline values (ΔQTcF).

It is to be understood that Bazett's (QTcB) formula, QTcB=QT/√RR, isanother commonly used correction formula but QTcF has been chosen herefor evaluation of QT prolongations instead of Bazett's formula becauseBazett's formula does not adequately correct for the effect of heartrate and is known to overcorrect at high heart rates. (see, e.g., DaveyP., “How to correct the QT interval for the effects of heart rate inclinical studies.” J. Pharmacol Toxicol Methods. 2002; 48; 3-9). It isalso to be understood that in double-blind clinical trials placeboadjusted change from baseline values of QTcF (ΔΔQTcF) however mean QTcFchange from baseline values (ΔQTcF) have been chosen for use here asthey do not require a double-blind protocol to determine and ECGmeasurements during normal clinical visits do not make use of placebos.

Modified Release Formulations

In various aspects and embodiments, the modified release compositions ina solid oral dosage form comprise amisulpride in the form of an unequalmixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride;and one or more pharmaceutically acceptable excipients. In variousembodiments, the one or more pharmaceutically acceptable excipientsinclude one or more extended release agents.

In various aspects and embodiments, the amisulpride comprises one ormore amisulpride enantiomers of crystalline Form A and/or Form A′.

In various embodiments, the modified release compositions make use of adistinct polymorphs of (R)-(+)-amisulpride and (S)-(−)-amisulpride;referred to as Form A for the free base crystalline form of(R)-amisulpride, and Form A′ for the free base crystalline form of(S)-amisulpride, and described in further detail herein. In variousembodiments the enantiomeric amisulpride is provided in one or more ofhigh polymorph purity, chiral purity, and chemical purity. In variousembodiments, one or both of the active pharmaceutical ingredients(R)-amisulpride and (S)-amisulpride are crystalline compounds,respectively, of Form A and Form A′.

It is to be understood that when an amisulpride enantiomer is said to bepresent in a certain weight amount, and such enantiomeric amisulpride isprovided as a pharmaceutically acceptable salt thereof, that the weightamount refers to the amisulpride enantiomer portion exclusive of thesalt portion, that is as the free base. Accordingly, it is to beunderstood that when a weight ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is recited, it is the weight ratios only of theamisulpride portions exclusive of any salt portion especially if onlyone of the amisulpride enantiomers is present as a pharmaceuticallyacceptable salt thereof or the amisulpride enantiomers are present asdifferent pharmaceutically acceptable salts.

In various aspects and embodiments, the modified release compositioncomprises a total amount of amisulpride between about 25 mg and about1000 mg, between about 50 mg and about 750 mg, between about 50 mg andabout 300 mg, or between about 100 mg and about 300 mg.

In various embodiments, the compositions comprise a ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, that is in the range between about 65:35 toabout 90:10 by weight of the free base, between about 80:20 to about88:12 by weight of the free base, or about 85:15 by weight of the freebase.

In various aspects and embodiments, the modified release compositionscomprise a total amount of amisulpride from about 100 mg to about 1000mg, from about 150 mg to about 800 mg, from about 100 mg to about 150mg, from about 150 mg to about 200 mg, from about 200 mg to about 300mg, from about 300 mg to about 400 mg, from about 400 mg to about 500mg, from about 600 mg to about 700 mg, from about 700 mg to about 800mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500mg, about 600 mg, about 700 mg, or about 800 mg, by weight of the freebase. In such compositions, the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is in the range between about 65:35 to about 90:10by weight of the free base, between about 80:20 to about 88:12 by weightof the free base, or about 85:15 by weight of the free base.

In various aspects and embodiments, the modified release compositionscomprise about 85 mg to about 600 mg of (R)-(+)-amisulpride, orpharmaceutically acceptable salts thereof, by weight of the free base;about 15 mg to about 100 mg of (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, by weight of the free base; wherein theenantiomeric ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride in themodified release compositions is about 65:35 to about 88:12 by weight ofthe free base.

In various aspects and embodiments, the modified release compositionscomprise about 170 mg to about 340 mg of (R)-(+)-amisulpride, orpharmaceutically acceptable salts thereof, by weight of the free base;about 30 mg to about 60 mg of (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, by weight of the free base; wherein theenantiomeric ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride in themodified release compositions is about 65:35 to about 88:12 by weight ofthe free base.

In various aspects and embodiments, the modified release compositionscomprise an amount about 170 mg of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of the free base;and an amount about 30 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of the free base.

In various aspects and embodiments, the modified release compositionscomprise an amount about 340 mg of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of the free base;and an amount about 60 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of the free base.

In various aspects and embodiments, the modified release compositionscomprise (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, in a ratio of R-amisulprideto S amisulpride from about 65:35 to about 90:10; from about 75:25 toabout 88:12, and from about 80:20 to about 88:12, by weight of the freebase.

In various aspects and embodiments, the ratio of (R)-amisulpride to(S)-amisulpride, or pharmaceutically acceptable salts thereof, is about65:35, about 66:34, about 67:33, about 68:32, about 69:31, about 70:30,about 71:29, about 72:28, about 73:27, about 74:26, or about 75:25, byweight of the free base.

In various aspects and embodiments, the ratio of (R)-amisulpride to(S)-amisulpride, or pharmaceutically acceptable salts thereof, is about80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15,about 86:14, about 87:13, about 88:12, about 89:11, or about 90:10, byweight of the free base.

In various aspects and embodiments, the ratio of (R)-amisulpride to(S)-amisulpride, or pharmaceutically acceptable salts thereof, is about80:20, by weight of the free base or about 85:15, by weight of freebase.

It is to be understood that pharmaceutically acceptable excipients,include, but are not limited to, one or more binders, bulking agents,buffers, fillers, stabilizing agents, surfactants, wetting agents,lubricating agents, diluents, disintegrants, plasticizers, viscosityenhancing or reducing agents, emulsifiers, anti-tacking agents,suspending agents, preservatives, antioxidants, opaquing agents,glidants, processing aids, colorants, sweeteners, taste-masking agents,perfuming agents, flavoring agents, diluents and other known additivesto provide an elegant presentation of the drug or aid in themanufacturing of a medicament or pharmaceutical product comprising themodified release compositions described herein. Examples of carriers andexcipients are described in detail in, e.g., Ansel, Howard C., et al.,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R.,et al. Remington: The Science and Practice of Pharmacy. Philadelphia:Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook ofPharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

In various aspects and embodiments the modified release compositionscomprise one or more pharmaceutically acceptable excipients, carriers,adjuvants, or vehicles, and are formulated as a solid oral dosage form.In various embodiments, the solid oral dosage form is in the form of apowder, tablet, caplet, or capsule. In various embodiments the solidoral dosage form comprises a tablet, and in various embodiments thesolid oral dosage form comprises a capsule.

In various embodiments, the modified release compositions are formulated(for example, with respect to active ingredient amounts) to beadministered once, twice, three times, or four times daily.

It is to be understood that the total amount of the amisulpride in theform of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, neednot be provided in a single dosage unit form, e.g. a single tablet,capsule, etc. In various embodiments, the modified release compositionis provided in dosage unit forms such that, for example, theadministration of two of the dosage unit forms will result inadministration of amisulpride in the desired combined amount of the(R)-amisulpride and (S)-amisulpride.

For example, various embodiments provide dosage unit forms comprising atotal combined amount of (R)-amisulpride and (S)-amisulpride of about100 mg (a 100 mg tablet/capsule), and comprising about 85 mg(R)-amisulpride and about 15 mg (S)-amisulpride. Accordingly,administration of two of these tablets/capsules, containing 100 mg ofamisulpride mixture, would result in administration of a total combinedamount of (R)-amisulpride and (S)-amisulpride of about 200 mg; whilstadministration of four of these tablets/capsules would result inadministration of a total combined amount of (R)-amisulpride and(S)-amisulpride of about 400 mg. It is further to be understood thatwith the addition of excipients and extended release agent a tabletcontaining 100 mg, for example, of amisulpride will weigh more than 100mg.

In various aspects and embodiments, all excipients comply with therespective The United States Pharmacopeia (USP), The JapanesePharmacopoeia (JP), Japanese Pharmaceutical Excipients (JPE), TheEuropean Pharmacopoeia (Ph. Eur.), and/or The National Formulary (NF)monograph.

The modified release compositions are in various embodiments formulatedin dosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the subject to be treated.

Tablet Formulations

In various embodiments, modified release compositions are provided assolid oral dosage forms in the form of a tablet comprising anintragranular component (granules) and an extragranular component; theintragranular component comprising (a) amisulpride in the form of amixture of (R)-amisulpride and (S)-amisulpride in a ratio of R:Samisulpride between 60:40 to 40:60; 65:35 to 90:10, 80:20 to 88:12, or85:15 by weight of the free base and (b) one or more pharmaceuticallyacceptable excipients; and the extragranular component comprising anextended release agent.

In various embodiments, the granules comprise between about 60% to about80% by weight of amisulpride in the form of a mixture of (R)-amisulprideand (S)-amisulpride, between about 10% to about 30% by weight of filler,between about 1% to about 5% by weight of binder; all weight percentagesbeing exclusive of any solvent (e.g. water) removed during processing.In various embodiments, the resultant tablet (granules plusextragranular component) comprises between about 20% to about 70% bytotal tablet weight of granules, between about 10% to about 50% by totaltablet weight of extended release agent, and a combined amount of bothextragranular and intragranular filler that is between about 6% to about60% by total tablet weight. In various embodiments, the combined amountof both extragranular and intragranular filler that is between about 10%to about 50% by total tablet weight.

In various embodiments, the granules comprise between about 60% to about80% by weight of the total of both enantiomers of amisulpride, betweenabout 10% to about 30% by weight of filler, between about 1% to about 5%by weight of binder; all weight percentages being exclusive of anysolvent (e.g. water) removed during processing.

In various embodiments, the granules comprise between about 70% to about80% by weight of the total of both enantiomers of amisulpride, betweenabout 20% to about 25% by weight of filler, between about 1% to about 5%by weight of binder; all weight percentages being exclusive of anysolvent (e.g. water) removed during processing.

In still further embodiments, the granules comprise between about 75% byweight of weight of the total of both enantiomers of amisulpride, about22% by weight of filler, about 3% by weight of binder; all weightpercentages being exclusive of any solvent (e.g. water) removed duringprocessing.

In various embodiments, the resultant tablet (granules plusextragranular component) comprises between about 20% to about 70% bytotal tablet weight of granules, between about 10% to about 50% by totaltablet weight of extended release agent, and a combined amount of bothextragranular and intragranular filler that is between about 6% to about60% by total tablet weight.

In various embodiments, the combined amount of both extragranular andintragranular filler is between about 10% to about 50% by total tabletweight. In some embodiments, the resultant tablet (granules plusextragranular component) comprises between about 20% to about 70% bytotal tablet weight of granules, between about 10% to about 50% by totaltablet weight of extended release agent, between about 0% to about 60%of extragranular filler, and between about 0% to about 2% of a lubricantby total tablet weight.

In various embodiments, the resultant tablet (granules plusextragranular component) comprises between about 45% to about 65% bytotal tablet weight of granules, between about 10% to about 35% by totaltablet weight of extended release agent, and between about 0% to about40% total tablet weight of extragranular filler, and between about 0% toabout 2% total tablet weight of a lubricant.

In various aspects and embodiments, the ratio of the weight percentageof both enantiomers of amisulpride relative to the total combined weightpercentage of the filler and binder in the granule is about 3:1.

In various aspects the ratio of the weight percentage of bothenantiomers of amisulpride relative to the total combined weightpercentage of the extragranular filler and extended release agent isabout 1:1 to 1:0.8.

In various aspects and embodiments, granulated granules exhibit a D50particle size of between about 180 microns to about 250 microns, betweenabout 170 microns to about 190 microns, between about 175 microns toabout 185 microns, between about 180 microns to about 205 microns,between about 205 microns to about 220 microns, or between about 220microns to about 240 microns.

In various aspects and embodiments, blended granules plus extragranularcomponent exhibit a D50 particle size of between about 180 microns toabout 250 microns. between about 80 microns to about 120 microns,between about 90 microns to about 110 microns, between about 180 micronsto about 205 microns, between about 205 microns to about 220 microns, orbetween about 220 microns to about 240 microns.

In still some further aspects and embodiments, the blended granules plusan extragranular component are compressed into tablets with acompression force of between 5-15 kN to produce tablets having ahardness between about 70 N and about 170 N.

In various embodiments of 200 mg Matrix Tablet Formulations,(R)-amisulpride, (S)-amisulpride and D-mannitol are separately delumpedwith a screen mill. The delumped (R)-amisulpride, delumped(S)-amisulpride, delumped D-mannitol, and partly pregelatinized starchare granulated by spraying aqueous solution of partially hydrolyzedpolyvinyl alcohol in a wet high-shear granulator, and wet granules arepassed through a screening mill to give sized granules. D-mannitol andhypromellose are blended with the sized granules in a blender.Subsequently, magnesium stearate is blended with the granules in ablender. The blended granules are compressed into core tablets with arotary press.

In various embodiments, examples of diluents and fillers include, butare not limited to, D-mannitol, dicalcium phosphate dibasic, dibasiccalcium phosphate, anhydrous dibasic calcium phosphate, lactose (e.g.,lactose monohydrate, lactose anhydrous, lactose monohydrate),microcrystalline cellulose, starch (e.g., pregelatinized starch, partlypregelatinized starch, and corn starch), powdered cellulose, andsorbitol. It is to be understood that more than one type of diluentand/or filler can be used in a tablet of the present inventions and thatthe diluent and/or filler in the granules can be the same or differentthan that used in the extragranular component of the tablet.

In various embodiments, examples of binders include, but are not limitedto, partially hydrolyzed polyvinyl alcohol, polyvinyl alcohol,methylcellulose, polyvinylpyrrolidone, copovidone, cellulosederivatives, shellac, zein, gelatin, polymethacrylates, syntheticresins, acrylates, and combinations thereof.

In various embodiments, the extended release agents include matrixformers such as cellulosic ethers, polymer coatings, polymer matrixsystems, enzyme-activated systems, and systems that respond to changesin physical conditions, such as pH, etc. Suitable polymers include, butare not limited to, pH independent polymers and pH dependent polymers.The extended release agent may be hydrophillic or hydrophobic in nature.It is to be understood that more than one type of extended release agentcan be used in an oral dosage form of the present inventions.

Examples of pH dependent polymers include, but are not limited to, analginate material, a carboxyvinyl polymer or sodium salts ofcarboxymethyl cellulose.

Examples of pH dependent polymers include, but are not limited to,hydroxy propyl methyl cellulose, hydroxy propyl ethyl cellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, methyl cellulose, xanthamgum, polyethylene oxide, ammonio methacrylate copolymers type A and B asdescribed in USP, polyacrylate dispersion 30% as described in Ph. Eur.,or combinations thereof.

In various embodiments, examples of extended release agents include, butare not limited to, hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC)(a.k.a. hypromellose), used alone or incombination with other extended release agents.

In various embodiments, used together with one or more disintegrants,such as, for example, croscarmellose sodium and crospovidone, to adjustthe release profile. For example, in various embodiments, thehydrophillic polymer will act as matrix to retard the dissolution of thesolid oral dosage form and one or more disintegrants absorb water tospeed hydration of a hydrophillic matrix.

In various embodiments, examples of glidants and anti-tacking agentsinclude, but are not limited to, Aerosil 200, light anhydrous silicicacid, colloidal silica, talc, calcium silicate, magnesium silicate,colloidal silicondioxide, and combinations thereof.

In various embodiments, examples of lubricants include, but are notlimited to, magnesium stearate, sodium stearyl fumarate, talc (e.g.,micronized talc), and combinations thereof.

In various embodiments, examples of lubricants include, but are notlimited to, magnesium stearate, sodium stearyl fumarate, talc,polyethylene glycol, calcium stearate, aluminum stearate, potassiumstearate, zinc stearate, talc (e.g., micronized talc), sodium stearylfumarate, silica, hydrogenated castor oil, hydrated silicon dioxide,magnesium silicate, light anhydrous silicic acid, synthetic aluminumsilicate, heavy anhydrous silicic acid, silicon dioxide, carnauba wax,titanium oxide, and combinations thereof.

In various embodiments, examples of surfactants include, but are notlimited to, sodium dodecyl sulfate, ammonium lauryl sulfate, other alkylsulfates, dodecyl betaine, dodecyl dimethylamine oxide, alkylpolyethylene oxide, copolymers of polyethylene oxide, and copolymers ofpolypropylene oxide, (alternatively called poloxamers). Additionalsurfactants include polyethoxylated tocopheryl succinate,polyoxyethylene castor oil, polyethoxylated castor oil, polyoxyethylenesorbitan monolaurate (Tween®20), polyoxyethylene sorbitan monopalmitate(Tween®40), polyoxyethylene sorbitan monostearate (Tween®60),polyoxyethylene sorbitan monooleate (Tween®80), polyethylene glycolmonostearate (Polyoxyl 40 stearate).polyoxyethylene-polyoxypropylenecopolymers, octylphenolethoxylate, and combinations thereof.

In various embodiments, examples of plasticizers include, but are notlimited to, one or more of triethyl citrate, PEG 6000, PEG8000, glycerylmonopalmetostearate, glyceryl monostearate, dibutyl phthalate, macrogol,triethyl citrate, polyethylene glycol, propylene glycol, polypropyleneglycol, sorbitol sorbitan solution, triacetin, glycerin, glycerol fattyacid, glycerol esters of fatty acids, silicon oil, acetyltriethylcitrate, diethyl phthalate, tributyl citrate, dibutyl phthalate,acetyltributyl citrate, dibutyl sebacate, glycerol triacetate,acetylated monoglyceride, and combinations thereof.

In various embodiments, one or more of ethylcellulose andaminoalkylmethacrylate copolymer RS are the polymers, and triethylcitrate is the plasticizer.

In is to be understood that pharmaceutical compositions, and inparticular solid oral dosage forms can comprise coatings, such a films,for example as an aid in swallowing or to maintain dosage form integrityupon handling, and such customary coatings are included in variousembodiments of the present inventions. In various embodiments, suchcoatings comprise one or more coating agents, colorants (a.k.a. coloringagents), opaquing agents (a.k.a. opacifiers), polishing agents, etc.

In various embodiments, examples of opaquing agents and colorantsinclude, but are not limited to, titanium oxide, titanium dioxide, ironoxide yellow (a.k.a. yellow ferric oxide), iron oxide red (a.k.a. redferric oxide), and talc, and combinations thereof.

In various embodiments, the modified release tablets have a compositionsubstantially in accord with that set forth in Table 1. The tablets ofTable 1 each comprise 200 mg of amisulpride in the form of a mixture of(R)-amisulpride and (S)-amisulpride, where (R)-amisulpride and(S)-amisulpride are in the ratio R:S of 85:15, and varying amounts ofextended release agent.

TABLE 1 Compositions Matrix Tablets 200 mg Lot 1A Lot 2A Lot 3A (10%)(15%) (45%) Component Function mg/tab mg/tab mg/tab Intra-(R)-amisulpride API 170 170 170 granular (S)-amisulpride API 30 30 30component D-Mannitol^(*1) Filler 29.5 29.5 29.5 Pregelatinized starchFiller 29.5 29.5 29.5 Polyvinyl alcohol Binder 5.5 5.5 5.5 Purifiedwater^(*2) Solvent 72 72 72 (binder solvent) Subtotal (granulecomponent)^(*5) 264.5 264.5 264.5 Extra- Hypromellose^(*3) Extended 50.075.0 225.5 granular release component agent D-Mannitol^(*4) Filler 178.0153.0 2.5 Magnesium stearate Lubricant 7.5 7.5 7.5 Total tablet weight500 500 500 ^(*1)Crystalline powder, Pearlitol 50C (Roquette) ^(*2)Wateris removed during processing. ^(*3)Metolose SR 90SH-100SR (Shin Etsu)^(*4)Spray dried powder, Pearlitol 100SD (Roquette) ^(*5)After waterremoved during processing

In various embodiments, the modified release tablets having acomposition substantially in accord with that set forth in Table 2. Thetablets of Table 2 each comprise 200 mg of amisulpride in the form of amixture of (R)-amisulpride and (S)-amisulpride where (R)-amisulpride and(S)-amisulpride are in the ratio R:S of 85:15, and varying amounts ofextended release agent.

TABLE 2 Compositions Matrix Tablets 200 mg Lot 1B Lot 2B Lot 3B Lot 4BLot 5B (10%) (15%) (25%) (35%) (45%) Component Function mg/tab mg/tabmg/tab mg/tab mg/tab Intra- (R)-amisulpride API 170 170 170 170 170granular (S)-amisulpride API 30 30 30 30 30 component D-Mannitol^(*1)Filler 29.5 29.5 29.5 29.5 29.5 Partly pregelatinized Filler 29.5 29.529.5 29.5 29.5 starch Polyvinyl alcohol Binder 8 8 8 8 8 Purifiedwater^(*2) Solvent 72 72 72 72 72 (binder solvent) Subtotal (granulecomponent)^(*5) 267.0 267.0 267.0 267.0 267.0 Extra- Hypromellose^(*3)Extended 50.0 75.0 125.0 175.0 225.5 granular release component agentD-Mannitor^(*4) Filler 175.5 150.5 100.5 50.5 − Magnesium stearateLubricant 7.5 7.5 7.5 7.5 7.5 Total tablet weight (mg) 500 500 500 500500 ^(*1): Crystalline powder, Pearlitol 50C (Roquette) ^(*2): Water isremoved during processing. ^(*3): Metolose SR 905H-100SR (Shin Etsu)^(*4): Spray dried powder, Pearlitol 100SD (Roquette) ^(*5): After waterremoved during processing

In various embodiments, the modified release tablets have a compositionsubstantially in accord with that set forth in Tables 3A, 3B, 3C, 3D and3E. The tablets of Tables 3A and 3B each comprise 200 mg of amisulpridein the form of a mixture of (R)-amisulpride and (S)-amisulpride where(R)-amisulpride and (S)-amisulpride are in the ratio R:S of 85:15, andvarying amounts of extended release agent. The tablets of Tables 3C, 3Dand 3E comprise either 100 mg or 200 mg of amisulpride in the form of amixture of (R)-amisulpride and (S)-amisulpride where (R)-amisulpride and(S)-amisulpride are in the ratio R:S of 85:15.

TABLE 3A Compositions Matrix Tablets 200 mg Lot 1C Lot 2C Lot 3C (10%)(25%) (15%) Component Function mg/tab mg/tab mg/tab Intra-(R)-amisulpride API 170 170 170 granular (S)-amisulpride API 30 30 30component D-Mannitol^(*1) Filler 29.5 29.5 29.5 Pregelatinized starchFiller 29.5 29.5 29.5 Polyvinyl alcohol Binder 5.5 5.5 5.5 Purifiedwater^(*2) Solvent 72 72 72 (binder solvent) Subtotal (granulecomponent)^(*5) 264.5 264.5 264.5 Extra- Hypromellose^(*3) Extended 50.0125.0 75.0 granular release agent component D-Mannitol^(*4) Filler 178.0103.0 153.0 Magnesium stearate Lubricant 7.5 7.5 7.5 Total tablet weight(mg) 500 500 500 ^(*1)Crystalline powder, Pearlitol 50C (Roquette)^(*2)Water is removed during processing. ^(*3)Metolose SR 90SH-100SR(Shin Etsu) ^(*4)Spray dried powder, Pearlitol 100SD (Roquette)^(*5)After water removed during processing

TABLE 3B Compositions Matrix Tablets 200 mg Lot 5C Lot 6C (20%) (40%)Component Function mg/tab mg/tab Intra-granular (R)-amisulpride API 170170 component (S)-amisulpride API 30 30 D-Mannitol^(*1) Filler 29.5 29.5Pregelatinized starch Filler 29.5 29.5 Polyvinyl alcohol Binder 5.5 5.5Purified water^(*2) Solvent 72 72 (binder solvent) Subtotal (granulecomponent)^(*5) 264.5 264.5 Extra- Hypromellose^(*3) Extended 100.0200.0 granular release agent component D-Mannitol^(*4) Filler 128.0 28.0Magnesium stearate Lubricant 7.5 7.5 Total tablet weight 500 500^(*1)Crystalline powder, Pearlitol 50C (Roquette) ^(*2)Water is removedduring processing. ^(*3)Metolose SR 90SH-100SR (Shin Etsu) ^(*4)Spraydried powder, Pearlitol 100SD (Roquette) ^(*5)After water removed duringprocessing

TABLE 3C Compositions Matrix Tablets 100 mg and 200 mg Quantity (mg/tab)Lot 7C Lot 8C Lot 9C Lot 10C (25%) (25%) (25%) (25%) Round, 11 mm Oval,11.2 × 8.7 mm Tablet shape, dimensions Function mg/tab mg/tab mg/tabmg/tab Intra-granular (R)-amisulpride API 85 170 85 170 component(S)-amisulpride API 15 30 15 30 D-Mannitol ^(*1) Filler 14.75 29.5 14.7529.5 Pregelatinized starch Filler 14.75 29.5 14.75 29.5 Polyvinylalcohol Binder 4 8 4 8 Purified water ^(*2) Solvent q.s. q.s. q.s. q.s.Subtotal (granule component) ^(*5) 133.5 267 133.5 267 Extra-granularHypromellose ^(*3) Extended 125 125 100 100 component release agentD-Mannitol ^(*4) Filler 231.5 98 158.5 25 Aerosil 200 Glidant 2.5 2.5 22 Magnesium stearate Lubricant 7.5 7.5 6 6 Uncoated tablet weight 500500 400 500 Film coating HPMC (TC-5R) Coating agent 6.25 6.25 6 6component Macrogol 400 Coating agent 0.625 0.625 0.6 0.6 Titaniumdioxide Coating agent 3.125 3.125 3 3 Talc Coating agent 2.25 2.25 2.162.16 Iron oxide yellow Color 0.175 0.175 0.168 0.168 Iron oxide redColor 0.075 0.075 0.072 0.072 Carnauba wax Polishing 0.01 0.01 0.01 0.01agent Total film-coated tablet weight (mg) 512.51 512.51 412.01 412.01^(*1): Crystalline powder, Pearlitol 50C (Roquette) ^(*2): Water isremoved during processing, ^(*3): Metolose SR 905H-100SR (Shin Etsu)(viscosity: 100mPa. s) ^(*4): Spray dried powder, Pearlitol 100SD(Roquette) ^(*5): After water removed during processing q.s. meansquantum sufficiat (as much as necessary)

TABLE 3D Compositions Matrix Tablets 100 mg and 200 mg Quantity (mg/tab)Lot 11C Lot 12C Lot 13C Lot 14C (25%) (25%) (25%) (25%) 200 200 100 100Total API (mg) Function mg/tab mg/tab mg/tab mg/tab Intra-(R)-amisulpride API 170 170 85 85 granular (S)-amisulpride API 30 30 1515 component Mannitol^(*1) Filler 29.5 29.5 14.75 14.75 PartlyPregelatinized starch^(*6) Filler 29.5 29.5 14.75 14.75Polyvinylalcohol^(*7) Binder 8 8 4 4 Purified water^(*2) Solvent q.s.q.s. q.s. q.s. Subtotal (granule component) ^(*5) 267 267 133.5 133.5Extra- Hypromellose^(*3) Extended 125 125 125 125 granular releasecomponent agent Mannitol^(*4) Filler 95.5 95.5 114 114 PartlyPregelatinized Filler — — 115 115 starch^(*8) Light anhydrous silicicGlidant 2.5 2.5 2.5 2.5 acid (Aerosil200) Sodium stearyl Lubricant 10 1010 10 fumarate (PRUV) Uncoated tablet weight 500 500 500 500 Filmcoating Hypromellose (TC-5R) Coating agent 3.75 6.25 3.75 6.25 Macrogol400 Coating agent 0.375 0.625 0.375 0.625 Titanium dioxide Coating agent1.875 3.125 1.875 3.125 Talc Coating agent 1.35 2.25 1.35 2.25 Ironoxide yellow Color 0.105 0.175 0.105 0.175 Iron oxide red Color 0.0450.075 0.045 0.075 Purified water^(*2) Solvent q.s. q.s. q.s. q.s.Carnauba wax Polishing 0.01 0.01 0.01 0.01 Total film-coated tabletweight ^(*5) agent 507.51 512.51 507.51 512.51 ^(*1): Crystallinepowder, Pearlitol 50C (Roquette) ^(*2): Water is removed duringprocessing. ^(*3): Metolose SR 905H-100SR (Shin Etsu) ^(*4): Spray driedpowder, Pearlitol 100SD (Roquette) ^(*5): After water removed duringprocessing ^(*6): PCS PC-10 (Asahi Kasei) ^(*7): GOHSENOL EG-05P(Mitsubishi Chemical) ^(*8): Starch 1500G (Colorcon) q.s. means quantumsufficiat (as much as necessary)

TABLE 3E Compositions Matrix Tablets 100 mg and 200 mg Quantity (mg/tab)Lot 15C Lot16C Lot 17C Lot 18C (25%) (25%) (25%) (25%) 200 200 100 100Total API (mg) Function mg/tab mg/tab mg/tab mg/tab (R)-amisulpride API170 170 85 85 (S)-amisulpride API 30 30 15 15 Intra- Mannitol ^(*1)Filler 29.5 29.5 14.75 14.75 granular Partly Pregelatinized componentstarch ^(*6) Filler 29.5 29.5 14.75 14.75 Polyvinylalcohol ^(*7) Binder8 8 4 4 Purified water ^(*2) Solvent q.s. q.s. q.s. q.s. Subtotal(granule component) ^(*5) 267 267 133.5 133.5 Hypromellose ^(*3)Extended release 125 125 125 125 agent Mannitol ^(*4) Filler 100.5 100.5119 119 Extra- Partly Pregelatinized Filler — — 115 115 granular starch^(*8) component Light anhydrous silicic Glidant 2.5 2.5 2.5 2.5 acid(Aerosil200) Magnesium stearate Lubricant 5 5 5 5 Uncoated tablet weight500 500 500 500 Hypromellose (TC-5R) Coating agent 3.75 6.25 3.75 6.25Macrogol 400 Coating agent 0.375 0.625 0.375 0.625 Titanium dioxideCoating agent 1.875 3.125 1.875 3.125 Film coating Talc Coating agent1.35 2.25 1.35 2.25 Iron oxide yellow Color 0.105 0.175 0.105 0.175 Ironoxide red Color 0.045 0.075 0.045 0.075 Purified water ^(*2) Solventq.s. q.s. q.s. q.s. Carnauba wax Polishing agent 0.01 0.01 0.01 0.01Total film-coated tablet weight ^(*5) 507.51 512.51 507.51 512.51 ^(*1):Crystalline powder, Pearlitol 50C (Roquette) ^(*2): Water is removedduring processing. ^(*3): Metolose SR 905H-100SR (Shin Etsu) ^(*4):Spray dried powder, Pearlitol 100SD (Roquette) ^(*5): After waterremoved during processing ^(*6): PCS PC-10 (Asahi Kasei) ^(*7): GOHSENOLEG-05P (Mitsubishi Chemical) ^(*8): Starch 1500G (Colorcon) q.s. meansquantum sufficiat (as much as necessary)

TABLE 4 Composition IR Tablet (Lot 1D) of FIG. 1A and FIG. 1B Lot 1DComponent Function (mg/tablet) Core Tablet (R)-amisulpride API 170.0(S)-amisulpride API 30.0 D-Mannitol Filler 167.5 Partly pregelatinizedstarch Filler 100.0 Partially hydrolyzed polyvinyl alcohol Binder 10.0Purified water^(*2) Granulation Solvent q.s. Croscarmellose sodiumDisintegrant 15.0 Magnesium stearate Lubricant 7.5 Weight of Core tablet500.0 Film Coat Suspension Hypromellose Coating agent 3.78 Macrogol 400Coating agent 0.38 Titanium oxide Coating agent 1.89 Talc Coating agent1.36 Yellow ferric oxide Coloring agent 0.11 Red ferric oxide Coloringagent 0.05 Purified water Coating solvent q.s. Carnauba wax Polishingagent 0.01 Total Weight 507.58 q.s. means quantum sufficiat (as much asnecessary)

TABLE 4 provides the formulation of the immediate release tabletscomprising 200 mg of combined amount of (R)-amisulpride and(S)-amisulpride in the ratio (R:S) of 85:15, for which dissolution datais provided in FIGS. 1A and 1B.

In various aspects and embodiments, the modified release composition,when tested using a two-stage in vitro dissolution test set forth inTable 5 and the accompanying description, (a) releases no more thanabout 40% of amisulpride after 2 hours and releases greater than about80% of amisulpride in less than about 12 hours; (b) releases less thanabout 40% of amisulpride after 1 hour, releases more than about 20% andless than about 60% of amisulpride after 3 hours, and releases more thanabout 30% and less than 100% of amisulpride after 6 hours; (c) releasesless than about 30% of amisulpride after 1 hour, releases more thanabout 20% and less than about 60% of amisulpride after 3 hours, andreleases more than about 30% and less than about 75% of amisulprideafter 6 hours; (d) releases less than about 20% of amisulpride after 1hour, releases more than about 20% and less than about 50% ofamisulpride after 3 hours, and releases more than about 30% and lessthan about 75% of amisulpride after 6 hours; (e) releases more thanabout 30% and less than about 50% of amisulpride after 6 hours; (f)releases between about 30% and 75% of amisulpride after about 3 hours,and releases more than about 75% of amisulpride after about 12 hours; or(g) releases more than about 75% of amisulpride after about 6 hours.

TABLE 5 In-vitro Dissolution Test Parameters Modified Release TabletFormulations Medium: 0-60 minutes 500 mL 0.01M HCl, pH 2.0 For pH SwitchAdd 400 mL of 0.15M Na3PO4 (pre-heat to 37° C.), pH 6.8 ± 0.05Dissolution type: USP II(Paddles) Paddle Speed: 75 rpm Volume of Medium:0-60 minutes 500 mL 60 minutes onwards 900 mL Temperature: 37.0° C.(±0.5) Sampling time points: Stage 1: 0.5, 1 Stage 2: 1.5, 2, 3, 4, 6,8, 10, 12 hours followed by infinity for 1 hour @ 250 rpm Sampling Type:Automatic with filter 10 μm full flow Sampling Volume: 1.5 mL

The in vitro dissolution profiles of the modified release (MR)formulations in FIGS. 1A, 1B, 1C and 1D were acquired using a paddleapparatus substantially in accord with that described by the UnitedStates Pharmacopeia Convention (USP) Apparatus 2 of Chapter 711Dissolution; USP41-NF36 General Chapter <711> Dissolution. Theapparatuses were operated as described in Table 5. Amisulpride releasewas determined from 1.5 ml samples taken from the medium and analyzedusing HPLC with a Kinetex Biphenyl, 4.6×100 mm, 2.6 μm (P/N:00D-4622-E0) column and UV detector set to 280 nm at the time pointsindicated in the figures.

TABLE 6 In-vitro Dissolution Test Parameters IR Tablet FormulationsMedium: 1^(st) Fluid for dissolution test of JP, pH 1.2 (containingsodium chloride, hydrochloric acid, and water, e.g. 2.0 g of sodiumchloride, 7.0 mL of hydrochloric acid in water to make 1000 mL)Dissolution type: JP General Test <6.10> Apparatus 2 Paddle Speed: 50rpm (first 60 minutes) Volume of Medium: 900 mL Temperature: 37.0° C.(±0.5) Sampling time points: 5, 10, 15, 30, 45, 60 minutes (at 50 rpm)and 75 minutes (at 250 rpm) Sampling Type: Manual Sampling Volume: 5 mL

The in vitro dissolution profiles of the IR formulations in FIGS. 1A and1B were acquired using a paddle apparatus substantially in accord withthat described by the paddle method of Japanese Pharmacopeia (JP)General test<6.10>, which was harmonized with Ph. Eur. <2.9.3> and USP<711>. The apparatuses were operated as described in Table 6. The amountof amisulpride dissolved in the dissolution medium was determined byreversed phase isocratic HPLC method, using a Kinetex Biphenyl, 4.6×100mm, 2.6 μm (P/N: 00D-4622-E0) column and UV detector set to 280 nm atthe time points indicated in the figures.

The dissolution tests of the IR formulations was discontinued prior tothe 60 minute mark as all API (i.e. all (R)-amisulpride and(S)-amisulpride) had been released.

The data plotted in FIGS. 1A, 1B, 1C, and 1D are also provided,respectively, in Tables 7, 8, 9A and 9B below.

TABLE 7 Data of FIG. 1A IR Lot 1D Lot 1A (10%) Lot 2A (15%) Lot 3A (45%)Time (% API (% API (% API (% API (hours) released) released) released)released) 0 0 0 0 0 0.17 59 0.25 81 0.5 101 42.9 15.5 6.4 1 101 63.126.2 11.2 1.25 101 88.9 1.5 36.1 15.1 2 96.4 43.5 18.2 3 97.0 56.8 24.94 97.1 70.4 31.7 6 98.1 93.5 43.5 8 99.2 55.6 10 99.6 63.8 12 99.3 74.112.5 100.8 100.8 13 79.8

TABLE 8 Data of FIG. 1B (data is % API released vs Time) Time Lot 1D Lot1B Lot 2B Lot 3B Lot 4B Lot 5B (minutes) IR (10%) (15%) (25%) (35%)(45%) 0 0 0 0 0 0 0 10 59 15 81 30 101 21.9 14.9 14.1 10.4 6.1 60 10135.2 25.6 24.0 17.6 10.8 75 101 90 62.9 35.1 32.7 23.1 14.5 120 91.743.1 38.3 27.2 17.8 180 98.0 57.0 47.3 35.2 24.0 240 97.7 68.3 56.2 42.529.9 360 97.8 88.6 69.7 54.8 40.7 480 98.6 99.1 81.3 65.9 50.6 600 98.999.6 59.6 720 99.1 99.9 68.1 735 100.0 100.9 88.4

TABLE 9A Data of FIG. 1C (data is % API released vs Time) Time Lot 1C(10%) Lot 3C (15%) Lot 2C (25%) (hours) (% API released) (% APIreleased) (% API released) 0 0 0 0 0.5 54.1 15.3 8.7 1 84.8 26.3 15.81.5 99.6 36.4 22.6 2 98.9 43.8 27.5 3 98.8 57.9 37.4 4 98.9 70.5 47 698.9 91.5 63.3 8 99.1 99.8 77.6 10 100.0 100.0 89.2 12 99.3 98.4 97.2

TABLE 9B Data of FIG. 1D (data is % API released vs Time) Lot 3Z Lot 3ZLot 3Z Lot 3Z Time Lot 2Z Lot 4Z (25%) (25%) (25%) (25%) Lot 5Z Lot 6Z(hours) (10%) (15%) Part 1 Part 2 fed state* MAD/PET** (20%) (40%) 0 0 00 0 0 0 0 0 0.5 54.1 15.3 8.7 10.2 9.1 8.4 11.2 7.6 1 84.8 26.3 15.817.9 16.7 15.3 20 14.2 1.5 99.6 36.4 22.6 24.6 23.2 21.4 28.5 19.2 298.9 43.8 27.5 30.2 28.1 26.5 34.8 23.2 3 98.8 57.9 37.4 40.6 37.7 36.547 31.1 4 98.9 70.5 47 50.4 46.8 45.8 58.2 39 6 98.9 91.5 63.3 67.4 62.862.3 77.9 53.1 8 99.1 99.8 77.6 80.3 76.9 76.6 91.4 66.2 10 100.0 100.089.2 89.8 88.2 88 98.5 77.8 12 99.3 98.4 97.2 95.7 96.7 96.2 100.2 87.4*Tablet batch of Lot 3Z formulation used in fed state study of Example7A, Part 1 **Tablet batch of Lot 3Z formulation used in MAD / PETImaging study of Example 7B

TABLE 9C Data of FIG. 1E (data is % API released vs Time) Lot 7C Lot 8CTime (25%) (25%) (hours) 100 mg 200 mg 0 0 0 0.5 9.0 6.7 1 17.1 13.0 1.524.0 18.9 2 29.6 23.8 3 40.3 33.0 4 50.5 41.8 6 68.8 57.8 6.25 74.0 62.1

In various embodiments, the modified release composition has a releaseprofile substantially in accord with that for Lot 1A (of Table 1) inFIG. 1A, Lot 2A (of Table 1) in FIG. 1A, Lot 3A (of Table 1) in FIG. 1A,Lot 1B (of Table 2) in FIG. 1B, Lot 2B (of Table 2) in FIG. 1B, Lot 3B(of Table 2) in FIG. 1B, Lot 4B (of Table 2) in FIG. 1B, Lot 5B (ofTable 2) in FIG. 1B, Lot 1C (of Table 3A) in FIG. 1C, Lot 2C (of Table3A) in FIG. 1C, Lot 3C (of Table 3A) in FIG. 1C, Lot 7C (of Table 3C) inFIG. 1E, or Lot 8C (of Table 3C) in FIG. 1E, when tested using atwo-stage in vitro dissolution test set forth in Table 5 and theaccompanying description.

In various embodiments, the modified release composition has a releaseprofile substantially in accord with that for Lot 2Z (of Table 24A) inFIG. 1D, Lot 3Z (of Table 24A) in FIG. 1D, Lot 3Z (of Table 24A) in FIG.1D fed state batch, Lot 3Z (of Table 24A) in FIG. 1D MAD/PET imagingbatch, Lot 4Z (of Table 24A) in FIG. 1D, Lot 5Z (of Table 24B) in FIG.1D, or Lot 6Z (of Table 24B) in FIG. 1D, when tested using a two-stagein vitro dissolution test set forth in Table 5 and the accompanyingdescription.

A variety of procedures can be used to make the modified release tabletsdescribed herein. For example, the modified release tablets of Tables1-3A, 3B, 4, 24A, 24B and 25, were made as follows. The activepharmaceutical ingredients ((R)-amisulpride and (S)-amisulpride) andD-mannitol (Pearitol 50C) were separately delumped with a screen mill.The delumped API, delumped D-mannitol and partly pregelatinized starchwere granulated by spraying aqueous solution of partially hydrolyzedpolyvinyl alcohol in a wet high-shear granulator, and wet granules werepassed through a screening mill and dried in a fluid bed granulator. Theresultant granules were then passed through a screening mill to givesized granules. D-mannitol (Pearitol 100SD) and hypromellose were thenblended with the sized granules in a blender. Subsequently, magnesiumstearate was blended with the granules in a blender. The blendedgranules were then compressed into core tablets with a rotary press.

More specifically, prior to mixing the active pharmaceutical ingredients((R)-amisulpride and (S)-amisulpride) with the various excipients toform granules, the (R)-amisulpride and (S)-amisulpride are separatelydelumped. The delumping employed a Powrex (Quadro) Co mill QC-194S,configured with a round bar impeller and round holed screen havingscreen size 1.397 mm(055R), with a spacer size of 0.200, and theimpeller operated with a low rotating speed of 743 min⁻¹. D-Mannitol wasalso delumped by a similar procedure.

Granulation was achieved using a Powrex FM-VG-05 (total capacity: 5 L)Granulator, configured with a blade of straight type 35° (rotating at400 rpm), cross screws of 60 mm×3 plates, (rotating at 3000 rpm), sealair pressures of 30 NL/min (Blade), 20 NL/min (Cross screw), a two fluidnozzle spray gun (with spray gun nozzle size of 1.0 mm operated at aspray rate of 10 g/min, a spray air pressure of 0.03 MPa, and atemperature control jacket set as required for various steps in theprocess.

The binder was first prepared as a 10% solid concentration placed inpurified water is heated above 80° C. and partially hydrolyzed polyvinylalcohol was dissolved in the heated water by propeller mixer. Inaddition, as required, other excipients were delumped prior tocombination.

To produce granules and tablets substantially in accord with those ofTables 1-3A, 3B, 4, 24A, 24B and 25, the binder was added forintroduction via the spray guns, and delumped mannitol, partlypregelatinized starch, delumped (R)-amisulpride and delumped(S)-amisulpride were mixed briefly in a plastic bag. The resultantmixture was added to the granulator container and blended for 1 min.,then the sprayer started to start spraying the binder. After spraying,all granules in the container, including granules adhered on surface ofcontainer, blade, cross screw, lid, are scraped off and the loss ofwater on drying determined.

The resultant granules were then wet sized prior to combination with theextra-granular component. The granules were wet sized using a Powrex(Quadro) Co mill QC-194S, configured with a round bar impeller and roundholed screen having screen size: 3.962 mm(156R), with a spacer size of0.225, and the impeller operated with a low rotating speed of 900 min⁻¹.The granules were fed manually over 2-3 min (for a 300 g scale feed).

The wet sized granules were then dried using a Powrex FD-MP-01 (totalcapacity: 0.6-3 L), with an inlet air flow of 0.7-1.0 m³/hr having aninlet air temperature of 80° C. The wet sized granules were added to thecontainer and drying started. The drying was stopped when the outlet airtemperature reached 40° C., and the granules tested for loss of water;loss on drying (LOD) should be NMT 2.0%.

The granules and extra-granule components were blended using a Tsutsuiscientific instrument S-3 (V-blender, total capacity: 2 L) as follows.The sized granules were added to the container of the blender, then theextended release agent (e.g. hypromellose) and filler (e.g., D-mannitol)were added, and the material blended for 15 min at 40 rpm. A portion ofthe blended granules were removed and mixed with a lubricant (e.g.,magnesium stearate), the mixture passed through an appropriate sieve(e.g., a 850 μm sieve), and the sieved mixture added back to the blendercontainer, and blended for 5 min at 40 rpm.

The tablets of Tables 1-3A, 3B, 4, 24A, 24B and 25 were then formedusing a Rotary press Kikusui VEL2, with 11 mm, WR (22.0R, 5.5 R)tooling, operated at a compression speed of 20 rpm and the compressionforce adjusted to produce tablets having a hardness of about NLT 100N.

Multiparticulate Capsule (MUPS) Formulations

In various aspects and embodiments, modified release compositions areprovided as solid oral dosage forms in the form of a capsule comprisingmultiple coated particulates; the particulate component comprising (a)coated particulates of substantially enantiomerically pure(R)-amisulpride and (b) coated particulates of substantiallyenantiomerically pure (S)-amisulpride, where R and S amisulprideparticulates are combined in the capsule in a ratio of R:S amisulpridebetween 65:35 to 90:10, between 80:20 to 88:12, or about 85:15 by weightof free base. In various aspects and embodiments, the extended releaseagent comprises the coating, which facilitates or provides for modifiedrelease of the API.

In various embodiments, the coating of the (R)-amisulpride and(S)-amisulpride particles is substantially the same, and in variousembodiments, the coating of the (R)-amisulpride and (S)-amisulprideparticles differs. In various embodiments, the particulates are coatedwith one or more polymer coatings comprising between about 8% and about60%, between about 10% and about 45%, or between about 15% and about 30%by weight of the total particle weight.

It is to be understood that the weight percentage of the polymer coatcan also be described as the weight of the polymer coating (e.g.polymer+plasticizer) as a percentage of the weight of the uncoatedparticles. Accordingly, in various embodiments modified releasecompositions are provided as solid oral dosage forms in the form of acapsule comprising multiple coated particulates; the particulatecomponent comprising (a) coated particulates of substantiallyenantiomerically pure (R)-amisulpride and (b) coated particulates ofsubstantially enantiomerically pure (S)-amisulpride, R and S amisulprideparticulates combined in the capsule in a ratio of R:S amisulpridebetween 65:35 to 90:10, between 80:20 to 88:12, or a ratio of about85:15 by weight of amisulpride free base. In various embodiments, thecoating of the (R)-amisulpride and (S)-amisulpride is substantially thesame, and in various embodiments, the coating of the (R)-amisulpride and(S)-amisulpride particles differs. In various embodiments, theparticulates are coated with one or more polymer coatings comprisingbetween about 10% and about 60%, between about 10% and about 45%, orbetween about 15% and about 35% by weight of the uncoated particleweight.

In various embodiments, the coated particulates of substantiallyenantiomerically pure (R)-amisulpride and substantially enantiomericallypure (S)-amisulpride are combined in the capsule in a ratio of R:Samisulpride between 65:35 to 90:10, between 80:20 to 88:12, or about85:15 by weight of free base.

In various embodiments, the particulates comprise in addition to theAPI, a binder and optionally a lubricant excipient, the combined API,binder and lubricant particulates being coated with one or morepolymers. In various embodiments, the API comprises between about 35%and about 65% of the total coated particle weight, the binder comprisesbetween about 8% and about 20%, and in various embodiments between about9% and about 15%, of the total coated particle weight, the lubricantexcipient comprises between about 8% and about 20%, and in variousembodiments between about 9% and about 15%, of the total coated particleweight, and the polymer coating between about 10% and about 45% byweight of the total particle weight.

In various embodiments, the particulates comprise in addition to theAPI, a binder and optionally a lubricant excipient, and the combinedAPI, binder and lubricant particulates being coated with one or morepolymers. In various embodiments, the API comprises between about 40%and about 85% of the total uncoated particle weight (and in variousembodiments between about 65% and about 75% of the total uncoatedparticle weight), the binder comprises between about 8% and about 20%,and in various embodiments between about 9% and about 15%, of the totaluncoated particle weight, the lubricant excipient comprises betweenabout 8% and about 20%, and in various embodiments between about 9% andabout 15%, of the total uncoated particle weight, and the polymercoating between about 10% and about 60% by weight of the uncoatedparticle weight, and in various embodiments between about 10% and about45% by weight of the uncoated particle weight, and in variousembodiments between about 15% and about 35% by weight of the uncoatedparticle weight.

In various embodiments, the ratio of the API to polymer coating isbetween about 1:0.5 and 1:0.6. In various embodiments, the ratio of theAPI to binder is between about 1:0.2 and 1:0.25. In various furtherembodiments, the ratio of the API to polymer coating is between about1:0.5 and 1:0.6, and the ratio of the API to binder is between about1:0.2 and 1:0.25.

In various embodiments, examples of binders include, but are not limitedto, hydroxypropyl cellulose, hydroxypropyl methylcellulose, partiallyhydrolyzed polyvinyl alcohol, polyvinyl alcohol, methylcellulose,hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose,polyvinylpyrrolidone, copolyvidone, polyethylene glycol, polyvinylalcohol-acrylic acid-methyl methacrylate copolymer, vinylacetate-vinylpyrrolidone copolymer, polyvinyl alcohol-polyethyleneglycol-graft copolymer, pregelatinized starch, dextrin, dextran,pullulan, alginic acid, gelatin, pectin, and a mixture of one or morethereof. In various embodiments, one or more of hydroxypropyl celluloseand polyvinyl alcohol are used.

In various embodiments, examples of lubricant excipients include, butare not limited to, micronized talc, magnesium stearate, sodium stearylfumarate, hydrated silicon dioxide, magnesium silicate, light anhydroussilicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid,silicon dioxide, calcium stearate, aluminum stearate, potassiumstearate, zinc stearate, yellow ferric oxide, red ferric oxide, andtitanium oxide. In various embodiments, one or more of talc, magnesiumstearate and sodium stearyl fumarate are used.

In various embodiments, the polymer coating comprises one or more waterinsoluble polymers and one or more plasticizers mixed with the one ormore polymers. In various embodiments, examples of water insolublepolymers include, but are not limited to, ethylcellulose, acetylcellulose, aminoalkylmethacrylate copolymer RS, ethyl acrylate, andvinyl acetate resin. In various embodiments, examples of plasticizersinclude, but are not limited to, triethyl citrate, polyethylene glycol,propylene glycol, polypropylene glycol, sorbitol sorbitan solution,triacetin, glycerin, glycerol fatty acid, silicon oil, acetyltriethylcitrate, diethyl phthalate, tributyl citrate, dibutyl phthalate,acetyltributyl citrate, dibutyl sebacate, glycerol triacetate, andacetylated monoglyceride. In various embodiments, one or more ofethylcellulose and aminoalkylmethacrylate copolymer RS are the polymers,and triethyl citrate is the plasticizer. In various embodiments, thepolymer coating comprises a mixture of ethylcellulose and triethylcitrate where the weight ratio of ethylcellulose to triethyl citrate isin the range between about 3:1 to about 5:1 and in various embodimentsabout 4:1.

It is to be understood that in the present multiparticulate capsuleformulations the R-amisulpride and the S-amisulpride containingparticulates may be formulated and coated separately, and thensufficient portions of the R-amisulpride particulates and theS-amisulpride particulates are combined in a capsule to provide thedesired amount of amisulpride mixture and ratio of R:S amisulpride. Itis to be understood that if the percentage of amisulpride in a coatedparticulate differs between the R-amisulpride particulates and theS-amisulpride particulates (as may result from different uncoatedparticulate formulations and/or different amounts of polymer coating),then particulates are combined based on the weight of the amisulpride inthe respective particulates.

Accordingly, it is to be understood that the absolute weights of thecapsule formulations in Tables 10 and 11 are not indicative of theabsolute weights of the various components in a final multiparticulatecapsule comprising the desired amount of amisulpride and R:S ratio.However, the compositions of Tables 10 and 11 do provide the relativeratios of the various components in the respective particulates,R-amisulpride particulates in Table 10 and the S-amisulprideparticulates in Table 11, of the particulate components of amultiparticulate capsule in various embodiments.

In various embodiments, the unequal mixture of R-amisulpride andS-amisulpride has an R-amisulpride to S-amisulpride ratio between 65:35to 90:10, between 80:20 to 88:12, or about 85:15 by weight of free base.

In various embodiments, the modified release multiparticulate capsuleshave an R-amisulpride particulate relative component compositionsubstantially in accord with that set forth in Table 10; that is, theweight ratios of the various components in the R-amisulprideparticulates in the multiparticulate capsules are substantially inaccord with the ratios (not absolute weights) set forth in Table 10. Theabsolute amounts of the components of the compositions of Table 10 arethe amounts found in capsules made from the particulates, which werethen dissolution tested (as described further below). Each lot so testedcomprised the same amount of (R)-amisulpride and varying amounts ofpolymer coating.

In various embodiments, the present inventions provide modified releasepharmaceutical multiparticulate capsules having an S-amisulprideparticulate relative component composition substantially in accord withthat set forth in Table 11; that is, the weight ratios of the variouscomponents in the S-amisulpride particulates in the multiparticulatecapsules are substantially in accord with the ratios (not absoluteweights) set forth in Table 11. The absolute amounts of the componentsof the compositions of Table 11 are the amounts found in capsules madefrom the particulates, which were then dissolution tested (as describedfurther below). Each lot so tested comprised the same amount of(S)-amisulpride and varying amounts of polymer coating.

TABLE 10 Compositions R-Amisulpride Particulate Formulations Quantity(mg) Lot RC10 Lot RC40 Component Function IR particles (10%) (40%)(R)-amisulpride API 200 200 200 Hydroxypropyl Binder 44.0 44.0 44.0Cellulose Micronized Talc Lubricant 44.4 44.4 44.4 EthylcellulosePolymer in — 23.3 93.0 Polymer Coat Triethyl Citrate Plasticizer in —5.6 22.3 Polymer Coat Total Weight 288.4 317.2 403.8

TABLE 11 Compositions S-Amisulpride Particulate Formulations Quantity(mg) IR Lot SC10 Lot SC20 Lot SC30 Lot SC40 Lot SC50 Lot SC60 ComponentFunction particles (10%) (20%) (30%) (40%) (50%) (60%) (S)-amisulprideAPI 200 200 200 200 200 200 200 Hydroxypropyl Binder 44.0 44.0 44.0 44.044.0 44.0 44.0 Cellulose Micronized Lubricant 44.6 44.6 44.6 44.6 44.644.6 44.6 Talc Ethylcellulose Polymer in — 23.3 46.5 69.8 93.1 116.4139.6 Polymer Coat Triethyl Citrate Plasticizer in — 5.6 11.2 16.8 22.327.9 33.5 Polymer Coat Total Weight 288.6 317.5 346.3 375.2 404.04 432.9461.8

The particle size distributions for the particulates comprising theformulations of Tables 10 and 11 are shown in Tables 12 and 13,respectively. These particle size distributions were determined using asieve analysis; the particulates being shifted through a stack of wiremesh sieves (conforming to BS 410 and ISP 3310-1 standards and withnominal aperture opening sizes as indicated in columns 1 of Tables 12and 13) that are shaken to separate the particulates into discrete sizeranges.

Scanning electron microscope (SEM) images of the particulates of Table11 are shown, in FIGS. 2A-2C. SEM samples were sputter-coated with aPt—Pd alloy using an ion sputtering system (Hitachi E1030). The SEMimages were acquired using a Hitachi S-3400N scanning electronmicroscope.

TABLE 12 Particle Size Distribution (PSD) for Particulates inFormulations of Table 10 Fraction Percentage by Sieve Size Lot RC40Sieve size Microns IR Particles (40%) >500 0.25 0.0 >355 0.49 1.7 >2500.82 22.0 >212 24.96 35.0 >180 33.96 17.4 >125 27.33 21.3 >90 2.862.4 >63 1.64 0.3 Base/<75 0.49 0.0

TABLE 13 Particle Size Distribution (PSD) for Particulates inFormulations of Table 11 Fraction Percentage by Sieve Size Lot SC30 LotSC60 Sieve size Microns IR Particles (30%) (60%) >500 0.00 0.000.24 >355 1.49 1.98 1.72 >250 1.75 11.13 24.08 >212 20.45 40.6050.61 >180 43.14 36.88 17.94 >125 28.93 9.16 5.16 >90 1.24 0.25 0.25 >630.25 0.00 0.00 Pass 2.75 0.00 0.00 D50 (μm) 192.40 215.40 232.00

The in vitro dissolution profiles of the formulations in FIGS. 3A and 3Bwere acquired using a paddle apparatus substantially in accord with thatdescribed by the United States Pharmacopeia Convention (USP) Apparatus 2of Chapter 711 Dissolution; USP41-NF36 General Chapter <711>Dissolution. The apparatus was operated as described in Table 5 for theMR formulation dissolution data of FIGS. 3A and 3B. Amisulpride releasewas determined from 1.5 ml samples taken from the medium and analyzedusing HPLC with a Kinetex Biphenyl, 4.6×100 mm, 2.6 μm (P/N:00D-4622-E0) column and UV detector set to 280 nm at the time pointsindicated in the figures. The data plotted in FIGS. 3A and 3B is alsoprovided, respectively, in Tables 14 and 15 below.

TABLE 14 Data of FIG. 3A (data is % API released vs Time) Time (hours)IR Particles Lot RC10 (10%) Lot RC40 (40%) 0 0 0 0 0.5 89.3 82.9 21.5 195.5 89.7 33.1 1.5 99.6 99.7 44.6 2 98.3 98.2 48.0 3 98.4 98.6 55.0 498.6 98.7 60.8 6 99.1 99.1 69.3 8 99.2 99.3 76.1 10 99.4 99.5 81.3 1299.7 99.7 85.5 18 100.0 100.0 93.6

TABLE 15 Data of FIG 3B (data is % API released vs Time) Time IR LotSC10 Lot SC20 Lot SC30 Lot SC40 Lot SC50 Lot SC60 (minutes) Particles(10%) (20%) (30%) (40%) (50%) (60%) 0 0 0 0 0 0 0 0 30 91.4 79.5 41 20.912.5 7.1 3.8 60 95.3 81.0 56.5 33.9 24.1 17.2 10.0 90 98.2 83.3 68.951.6 33 24.1 15.4 120 98.5 84.7 74.6 62.6 37.4 26.6 17.3 180 98.6 86.080.7 76.2 44.4 30.5 20 240 98.7 87.0 84.3 83.4 50.4 33.8 22.2 360 98.788.5 89.7 89.9 59.6 39.6 26.1 480 99.6 90.0 92.8 92.2 66.7 44.8 29.5 49590.3 93.8 92.3 67.6 45.3 30.2

In various embodiments, the modified release multiparticulate capsuleshave a composition substantially in accord with that set forth in Tables16A and 16B. The capsules of Tables 16A and 16B each comprise 200 mg or100 mg of (R)-amisulpride and (S)-amisulpride in the ratio R:S of 85:15,and varying amounts of polymer coating for the particulates. Asdescribed herein, the multiparticulate capsules are produced bycombining appropriate amounts of polymer coated (R)-amisulprideparticulates and polymer coated (S)-amisulpride particulates within acapsule.

TABLE 16A Compositions Multiparticulate Capsules Lot C1A Lot C1B Lot C1CLot C1D (10%) (40%) (40%) (10%) Component Function mg mg mg mg(R)-amisulpride API 170.0 170.0 85.0 85.0 (S)-amisulpride API 30.0 30.015.0 15.0 Hydroxypropyl Binder 44.0 44.0 22.0 22.0 Cellulose MicronisedTalc Lubricant 44.4 44.4 22.2 22.2 Ethylcellulose Polymer Coat 23.2 93.046.5 11.6 Triethyl Citrate Polymer Coat 5.5 22.3 11.2 2.8 Total perCapsule 317.2 403.8 201.9 158.6 Gelatin Capsules Encapsulation 1 unit 1unit 1 unit 1 unit

TABLE 16B Lot C2A Lot C2B (22.5%) (30%) Component Function mg mg(R)-amisulpride API 170.0 170.0 (S)-amisulpride API 30.0 30.0Hydroxypropyl Cellulose Binder 44.0 44.0 Micronised Talc Lubricant 44.444.4 Ethylcellulose Polymer Coat 52.5 69.9 Triethyl Citrate Polymer Coat12.4 16.6 Total per Capsule 353.3 374.9 Gelatin Capsules Encapsulation 1unit 1 unit

Compositions Multiparticulate Capsules

TABLE 17 PSD for Particulates in Formulations of Lot C1B and C1C ofTable 16A Fraction Percentage by Sieve Size R-amisulpride particlesS-amisulpride particles Lot C1B and C1C Lot C1B and C1C Sieve sizeMicrons (40%) (40%) >500 0.0 0.1 >355 1.7 3.8 >250 22.0 30.7 >212 35.038.7 >180 17.4 14.4 >125 21.3 12.1 >90 2.4 0.2 >63 0.3 0.0 Base/<75 0.00.0

The particle size distributions for the particulates comprising theformulations of Lot C1B and Lot C1C in Table 16A are shown in Table 17.These particle size distributions were determined using a sieveanalysis; the particulates being shifted through a stack of wire meshsieves (with nominal aperture opening sizes as indicated in column 1 ofTable 17) that are shaken to separate the particulates into discretesize ranges.

The in vitro dissolution profiles of the formulations in FIG. 4A andFIG. 4B were acquired using a paddle apparatus described by the UnitedStates Pharmacopeia Convention (USP) Apparatus 2 of Chapter 711Dissolution; USP41-NF36 General Chapter <711> Dissolution. The apparatuswas operated as described in Table 5 for the MR formulation dissolutiondata of FIGS. 4A and 4B. Amisulpride release was determined from 1.5 mlsamples taken from the medium and analyzed using HPLC with a KinetexBiphenyl, 4.6×100 mm, 2.6 μm (P/N: 00D-4622-E0) column and UV detectorset to 280 nm at the time points indicated in the figures. The dataplotted in FIGS. 4A and 4B is also provided, respectively, in Tables 18Aand 18B below.

TABLE 18A Data of FIG. 4A (data is % API released vs Time) Time Lot C1DLot C1A Lot C1C Lot C1B (hours) (100 mg, 10%) (200 mg, 10%) (100 mg,40%) (200 mg, 40%) 0 0 0 0 0 0.5 71.2 73.2 11.8 14.9 1 84.2 82.7 22.326.1 1.5 100.9 95.7 33.8 35.4 2 97.9 95.3 36.2 39.0 3 98.7 96.3 41.445.4 4 99.0 97.1 46.7 50.8 6 99.2 97.8 54.5 59.7 8 99.9 98.7 62.7 67.110 99.3 99.1 68.9 73.0 12 99.8 99.4 74.4 78.0 18 100.0 100.0 85.3 87.4

TABLE 18B Data of FIG. 4B (data is % API released vs Time) Lot C2A LotC2B Time (hours) (22.5%) (30%) 0 0 0 0.5 28.6 14.2 1 46.8 26.0 1.5 66.135.8 2 76.1 39.9 3 87.6 47.5 4 93.4 54.0 6 98.0 64.2 8 99.9 72.2 10100.6 77.9 12 101.2 82.1 18 101.6 90.3

In various embodiments, the modified release multiparticulate capsulehas a dissolution profile substantially in accord with that for Lot C1Ain FIG. 4A, Lot C1B in FIG. 4A, Lot C1C in FIG. 4A, or Lot C1D in FIG.4A when tested using a two-stage in vitro dissolution test substantiallyas set forth in Table 5 and the accompanying description.

In various embodiments, the modified release multiparticulate capsulehas a dissolution profile substantially in accord with that for Lot C2Ain FIG. 4B, or Lot C2B in FIG. 4B when tested using a two-stage in vitrodissolution test substantially as set forth in Table 5 and theaccompanying description.

A variety of procedures can be used to make the modified releasecapsules described herein. For example, the (R)-amisulpride particulatesof Table 10, the (S)-amisulpride particulates of Table 11, and thecoated particulates of substantially enantiomerically pure(R)-amisulpride and coated particulates of substantiallyenantiomerically pure (S)-amisulpride used to make the modified releasecapsules of Tables 16A and 16B, were made as follows. The uncoatedsubstantially enantiomerically pure (R)-amisulpride particulates anduncoated substantially enantiomerically pure (S)-amisulprideparticulates were made separately using the same procedure; and coatedseparately to make modified release particulates using the sameprocedure.

The uncoated particulates were made by as follows. The activepharmaceutical ingredients ((R)-amisulpride and (S)-amisulpride) wereseparately delumped with a screen mill and the binder (hydroxypropylcellulose) was separately delumped with a sieving shaker. The delumpedactive pharmaceutical particulates ingredients were each separatelycombined with the delumped hydroxypropyl cellulose and micronized talc(lubricant), blended and then granulated by spraying purified water in awet high-shear granulator to make wet particulates, and wet particulateswere then dried in a fluid bed granulator. The resultant dryparticulates were sieved with sieving shaker to obtain the immediaterelease (IR) particulates. The resultant dry IR particulates were thencoated (each enantiomer separately) to make the modified release (MR)particulates for each enantiomer.

More specifically, prior to mixing the active pharmaceutical ingredients((R)-amisulpride and (S)-amisulpride) with the various excipients toform granules, the (R)-amisulpride and (S)-amisulpride are separatelydelumped. The delumping employed a Powrex (Quadro) Co mill QC-194S,configured with a round bar impeller and round holed screen havingscreen size 1.143 mm, and the impeller operated with a low rotatingspeed of 743 min⁻¹. The hydroxypropyl cellulose delumping employed anIIDA Sieving shaker (ES-65), with a 150 mmφ sieve, and sieve mesh sizesof 150 μm and 500 μM, with the shaking level rotating at 230 rpm andtapping at 130 rpm, and a total sieving time of 10 minutes.

Granulation was achieved using a Powrex FM-VG-05 (total capacity: 5 L)Granulator, configured with a blade of straight type 35° (rotating at400 rpm), cross screws of 60 mm×3 plates, (rotating at 3000 rpm), sealair pressures of 20 NL/min (Blade), 10 NL/min (Cross screw), a two fluidnozzle spray gun (with spray gun nozzle size of 0.5 mm ID, length ofnozzle tip to air cap of 0.5 mm and operated at a spray rate of 4 g/min,a spray air pressure of 0.08 MPa. It is to be understood that atemperature control jacket can be used and set as required for varioussteps in the process.

The procedure for granulation was as follows. The talc was added to thegranulator container and blended for 1 minute. The sieved hydroxypropylcellulose in propoer proportion was added to the delumped API((R)-amisulpride or (S)-amisulpride) in a plastic bag and mixed shortly.The resultant mixture was added to the granulator container (containingtalc) and blended for 3 minutes. The spray binder (purified water) wasthen started and sprayed in the following amounts and blended in thefollowing eleven aliquots: aliquot 1 sprayed 50 g; aliquot 2 sprayed 50g; aliquot 3 sprayed 25 g; aliquot 4 sprayed 0 g (blended for 5 min);aliquot 5 sprayed 15 g aliquot 6 sprayed 0 g (blended for 5 min);aliquot 7 sprayed 15 g; aliquot 8 sprayed 0 g (blended for 5 min);aliquot 9 sprayed 0 g (blended for 3 min); aliquot 10 sprayed 0 g(blended for 2 min); and aliquot 11 sprayed 0 g (blended for 2 min).After spraying, all granules in container including granules adhered onsurface of container, blade, cross screw, and lid, were scraped off andthe steps of spraying and blending for the 11 aliquots and scraping wererepeated. As mentioned previously, it is to be understood that thisprocess was carried out separately for each of the APIs ((R)-amisulprideand (S)-amisulpride), that is a given batch contained substantially onlya single amisulpride enantiomer.

After granulation, the resulting particulates were dried using a PowrexFD-MP-01 (Total capacity: 0.6-3 L) operated with an inlet air flow of0.79-0.91 m³/min, and an inlet air temperature of 80° C. The wetparticulates were added to the container and drying started. The dryingwas stopped when the outlet air temperature reached 40° C., and theparticulates tested for loss of water; loss on drying (LOD) should beNMT 2.0%.

The dried particulates were then sieved (separately for each enantiomer)using an IIDA Sieving shaker (ES-65), with a 150 mmφ sieve, and sievemesh sizes of 106 μm and 500 μm, with the shaking level rotating at 230rpm and tapping at 130 rpm, and a total sieving time of 10 minutes. Theresultant immediate release particulates were then coated to prepare theMR particulates.

Specifically, IR particulates of a single enantiomer were coated with aPowrex/FD-MP-01/SPC (Total capacity: 0.6-3 L) gas suspension/fluidizedbed apparatus in 650 g batches configured with an inlet air flow of0.77-0.94 m³/min, a SPC pulse air pressure of 0.2 MPa, a two fluidnozzle spray gun (with spray gun nozzle size of 1.2 mm ID, length ofnozzle tip to air cap of 2.0 mm and operated at a spray rate of 4 g/min,a spray air pressure of 0.2 MPa), and with preheating to provide aninitial inlet temperature of 67° C. and outlet target temperature of 38°C., that exhibited a range of 36-40° C. After preheating, the IRparticulates of a specific enantiomer were added to the container andgranulation and spraying started. Coating amount was monitored (ifnecessary) by weight and the granulator was stopped when the sprayedamount reached the desired coating level. As mentioned previously, it isto understood that this process was carried out separately for each ofthe APIs ((R)-amisulpride and (S)-amisulpride), that is a given batchcontained substantially only a single amisulpride enantiomer.

The coated particulates were then dried using a TABAI/perfect ovenPH-400 (a direct heating, static solid bed drier with tray and trucks)operated at 60° C., with metallic tray and a 1.5 cm thick particulatelayer on the tray, and dried for 18 hours. Subsequent to drying, theparticulates were sieved with a 500 μm sieve by hand.

(R)-(+)-amisulpride and (S)-(−)-amisulpride

The modified release formulations comprise unequal mixtures of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, where the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride.

In various embodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, is inthe range between about 65:35 to about 90:10 by weight of the free base,or about: 65:35, 66:34, 67:33, 68:32, 69:31, 70:30, 71:29, 72:28, 73:27,74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 81:19, 82:18, 83:17,84:16, 85:15, 86:14, 87:13, 88:12, 89:11, or 90:10, by weight of thefree base. In various embodiments, the ratio of (R)-amisulpride to(S)-amisulpride, or pharmaceutically acceptable salts thereof, is 85:15by weight. In various embodiments, the total combined amount of(R)-amisulpride and (S)-amisulpride in is about 50 mg, 75 mg, 100 mg,150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg,900 mg, or 1000 mg. In various embodiments, once administered, or asadministered over a treatment cycle, the total combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride ranges from about 50-1000 mgor from about 200-750 mg.

In various embodiments, the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, is ina ratio effective to provide in a subject after administration: anoccupancy of dopamine D2 receptors between about 20% and about 60%; anda suppression of time in rapid eye movement (REM) sleep ischaracterized, for example, by one or more of: (a) a decrease in REMsleep by an amount greater than about 10 minutes; (b) a latency to REMsleep by an amount greater than about 20 minutes, or (c) a decrease intotal REM sleep time relative to total sleep time by an amount greaterthan about 5%.

In various embodiments, the total combined amount of (R)-amisulpride and(S)-amisulpride is sufficient to cause a suppression of the time inrapid eye movement (REM) sleep by an amount between about 15 minutes andabout 60 minutes.

In various embodiments, the relative amounts of R and S amisulpride arechosen such that, upon release from the modified release pharmaceuticalcomposition, the D₂ occupancy is about 20% to about 60%. Occupanciesabove about 65% are associated with adverse events. Considering adverseevents, in some embodiments, the amount of S isomer in the compositionshould not exceed the amount necessary to achieve about 60% or about 50%D₂ occupancy upon release from the modified release pharmaceuticalcomposition. In some embodiments, the amount of S-amisulpride should bethe minimum to achieve about 20% to about 25% D₂ occupancy. In someembodiments, the amount of S-amisulpride should be the minimum toachieve about 25% to about 30% D₂ occupancy.

Dopamine D₂ receptor occupancy can be measured, for example, by D2Positron Emission Tomography (PET) in human brain through the averageoccupancy observed in a group of humans of sufficient number to providestatistical significance of the result. Suppression of REM sleep can bemeasured, for example, by polysomnography (PSG) in human subjectsthrough the average inhibition observed in a group of humans ofsufficient number to provide statistical significance of the result.

In various embodiments, the amount of R-amisulpride administered, uponrelease from the modified release composition, should be sufficient toachieve a reduction on the time a patient spends in REM sleep time of atleast about 10 minutes to about 45 minutes, about 15 minutes to 30minutes, or about 18 minutes to about 31 minutes.

Dosing of (S)-(−)-amisulpride, upon release from the modified releasecomposition, should be sufficient to achieve a D₂ occupancy level ofbetween about 20% and about 60% to achieve the desired therapeuticeffect with reduced adverse events. At levels above about 70% to about75% the adverse events occur at an increasing frequency and severity.Higher dosing levels to achieve a greater D₂ occupancy can be used ifthe patient does not experience an unacceptable level of adverse events.Typical daily doses of (S)-(−)-amisulpride are from about 5 mg to about150 mg, about 10 mg to about 150 mg, or about 15 mg to about 100 mg, orin various embodiments the daily dose is from about 20 mg to about 35mg. All doses are as the free base. The doses may be administered in asingle daily dose or in divided doses.

Typical daily doses of (R)-(+)-amisulpride free base are from about 50mg to about 1000 mg, about 100 mg to about 600 mg, about 100 mg to about300 mg, or about 130 mg to about 180 mg. All doses are as the free base.The doses may be administered in a single daily dose or in divideddoses.

In various embodiments, the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, is ina ratio effective to provide in a subject after administrationinhibition of dopamine D₂ activity and serotonin 5-HT₇ activity in saidsubject such that the ratio of the serotonin 5-HT₇ receptor inhibitoryconstant to the dopamine D₂ receptor inhibitory constant is in the rangebetween about 2 to about 6, between about 3 to about 5, or about 4.

In various embodiments, the dopamine D2 receptor inhibitory constant isin the range between about 11 nM to about 20 nM and the serotonin 5-HT7receptor inhibitory constant is in a range between about 40 nM to about85 nM. In various embodiments, the dopamine D2 receptor inhibitoryconstant is in the range between about 15 nM to about 20 nM and theserotonin 5-HT7 receptor inhibitory constant is in a range between about50 nM to about 80 nM. In various embodiments, the dopamine D2 receptorinhibitory constant is about 17 nM and the serotonin 5-HT7 receptorinhibitory constant is about 66 nM.

In various embodiments, where the ratio of (R)-amisulpride to(S)-amisulpride, or pharmaceutically acceptable salts thereof, iseffective to provide in a subject after administration inhibition ofdopamine D2 activity and serotonin 5-HT7 activity in said subject suchthat the ratio of the serotonin 5-HT7 receptor inhibitory constant tothe dopamine D2 receptor inhibitory constant is in the range betweenabout 2 to about 6, and in various embodiments between about 3 to about5; the ratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, by weight is: about 80:20, about 81:19, about82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13,about 88:12, about 89:11, or about 90:10; and in various embodimentsabout 85:15 by weight of the free base.

In various embodiments, the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride over a treatment cycle is about 85:15 by weight, thetreatment cycle is daily and the total amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is 200 mg or 400 mg over the treatment cycle.

In various embodiments, the total combined amount of (R)-amisulpride and(S)-amisulpride in a modified release pharmaceutical composition, onceadministered to a subject, or as administered to a subject over atreatment cycle, is sufficient to provide an occupancy of dopamine D₂receptors between about 20% and about 60%; and a suppression of time inrapid eye movement (REM) sleep characterized, for example, by one ormore of: (a) a decrease in REM sleep by an amount greater than about 10minutes; (b) a latency to REM sleep by an amount greater than about 15minutes, or (c) a decrease in total REM sleep time relative to totalsleep time by an amount greater than about 5%.

In various embodiments, the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, is effective to provide anoccupancy of dopamine D₂ receptors between about 30% and about 50%.

In various embodiments, the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, is effective to provideone or more of: (i) a decrease in REM sleep by an amount greater thanabout 10 minutes; (ii) a decrease in REM sleep by an amount greater thanabout 20 minutes; (iii) a decrease in REM sleep by an amount betweenabout 15 minutes and about 45 minutes; and (iv) a decrease in REM sleepby an amount between about 15 minutes and about 30 minutes.

In various embodiments, the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, is effective to provideone or more of: (i) a decrease in total REM sleep time relative to totalsleep time by an amount greater than about 5%; (ii) a decrease in totalREM sleep time relative to total sleep time by an amount greater thanabout 6.5%; and (iii) a decrease in total REM sleep time relative tototal sleep time by an amount greater than about 8%.

In various embodiments, the combined amount of (R)-amisulpride and(S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg,200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg,425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg,650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg,875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg, by weight of thefree base.

In various embodiments, the combined amount of (R)-amisulpride and(S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg,200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg,425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg,650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg,875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg, by weight of thefree base, and wherein the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, by weight is about: 65:35,66:34, 67:33, 68:32, 69:31, 70:30, 71:29, 72:28, 73:27, 74:26, 75:25,76:24, 77:23, 78:22, 79:21, 80:20, 81:19, 82:18, 83:17, 84:16, 85:15,86:14, 87:13, 88:12, 89:11, or 90:10; and in various embodiments 85:15by weight of the free base.

Methods of Treatment

The medicaments and modified release compositions can be used to treat,and/or used to manufacture a medicament to treat, a psychiatric disorderin a subject, a neurological disorder in a subject, or both aneurological disorder and a psychiatric disorder, the disorderincluding, but not limited to, one or more of a mood disorder, bipolardisorder (BPD), depression, bipolar depression, major depressiveepisodes associated with bipolar I disorder, major depressive disorder(MDD), as an adjunctive treatment of major depressive disorder; majordepressive disorder with mixed features (MDD-MF), treatment resistantdepression (TRD), schizophrenia, negative symptoms of schizophrenia, andschizoaffective disorder.

In various aspects and embodiments, there is provided a method oftreating a psychiatric disorder in a subject comprising administering tothe subject a modified release composition in a solid oral dosage formcomprising amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride; and one or morepharmaceutically acceptable excipients. In various embodiments, the oneor more pharmaceutically acceptable excipients include one or moreextended release agents. In various embodiments, the psychiatricdisorder is bipolar disorder and/or depression associated with bipolardisorder. The ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, may be in the range betweenabout 65:35 to about 90:10, about 80:20 to about 88:12, or about 85:15by weight of the free base; and one or more pharmaceutically acceptableexcipients. In various embodiments, the one or more pharmaceuticallyacceptable excipients include one or more extended release agents.

In various embodiments of the method of treating:

(1) the modified release composition is administered in amounts betweenabout 200 mg to about 400 mg per day of amisulpride by weight of freebase as a solid oral dosage form, and in various embodiments once perday; and/or

(2) the modified release composition when administered to a subjectpopulation provides a population average maximum QT intervalprolongation over the time period of 12 hours after administration of:(a) less than about 0.45 milliseconds (ms) per 10 mg of amisulpride; (b)less than about 0.30 milliseconds (ms) per 10 mg of amisulpride; (c)less than about 0.20 milliseconds (ms) per 10 mg of amisulpride; (d)less than about 0.15 milliseconds (ms) per 10 mg of amisulpride; (e)less than about 0.10 milliseconds (ms) per 10 mg of amisulpride t; (f)less than about 0.05 milliseconds (ms) per 10 mg of amisulpride; or (g)less than about 0.02 milliseconds (ms) per 10 mg of amisulpride; and/or

(3) the modified release composition when administered to a subjectpopulation provides a population average maximum QTcF intervalprolongation over the time period of 12 hours after administration of:(a) less than about 10 milliseconds (ms); (b) less than about 9milliseconds (ms); (c) less than about 8 milliseconds (ms); (d) lessthan about 7 milliseconds (ms); (e) less than about 6 milliseconds (ms);or (f) less than about 5 milliseconds (ms); and/or

(4) the modified release composition when administered to a subjectpopulation provides a population average maximum QT intervalprolongation over the time period of 12 hours after administration, thatcompared to a comparable immediate release formulation is: (a) at leastabout 75% less than that of said immediate release composition; (b) atleast about 65% less than that of said immediate release composition;(c) at least about 60% less than that of said immediate releasecomposition; (d) at least about 55% less than that of said immediaterelease composition; or (e) at least about 50% less than that of saidimmediate release composition; and/or

(5) the modified release composition when administered to a subjectpopulation provides about 27 hours after said administration apopulation average occupancy of dopamine D₂ receptors between about 20%and about 60%; and/or

(6) the modified release composition when administered to a subjectpopulation provides a population average occupancy of dopamine D2receptors that, compared to an immediate release composition having thesame total daily amount of amisulpride as the pharmaceuticalcomposition, is (a) at least 85% of the dopamine D2 receptors occupancyof said immediate release composition; (b) at least 90% of the dopamineD2 receptors occupancy of said immediate release composition; or (c) atleast 95% of the dopamine D2 receptors occupancy of said immediaterelease composition; and/or

(7) the modified release composition when administered to a subjectpopulation provides, compared to an immediate release composition havingthe same total daily amount of amisulpride as the pharmaceuticalcomposition, (A) a population average occupancy of dopamine D2 receptorsat about 27 hours after administration that is at least 85% of thedopamine D2 receptors occupancy of said immediate release composition,(B) a blood plasma Cmax of amisulpride that is less than about 80% ofthe Cmax of said immediate release composition; and (C) a AUC from 0 to24 hours after administration (AUC₀₋₂₄) of amisulpride that is (a) lessthan about 80% of the AUC₀₋₂₄ of said immediate release composition;and/or

(8) the solid oral dosage form, when dissolution tested using atwo-stage in vitro gastrointestinal simulation dissolution testdescribed in Table 5, releases (a) less than about 40% of amisulprideafter 1 hour, more than about 20% and less than about 60% of amisulprideagent after 3 hours, and more than about 30% and less than 100% ofamisulpride after 6 hours; (b) less than about 30% of amisulpride after1 hour, more than about 20% and less than about 60% of amisulpride after3 hours, and more than about 30% and less than about 75% of amisulprideafter 6 hours; (c) less than about 20% of amisulpride after 1 hour, morethan about 20% and less than about 50% of amisulpride after 3 hours, andmore than about 30% and less than about 75% of amisulpride after 6hours; (d) more than about 30% and less than about 50% of amisulprideafter 6 hours; (e) between about 30% and 75% of amisulpride after about3 hours and more than about 75% of amisulpride after about 12 hours; or(f) more than about 75% of amisulpride after about 6 hours; and/or

(9) the modified release composition, when administered to a subjectpopulation, is effective in minimizing fluctuations between Cmin andCmax of amisulpride; and/or

(10) the modified release composition used in treating the psychiatricdisorder is effective in minimizing the difference between Cmin and Cmaxof amisulpride compared to the immediate release composition having thecomposition of Table 25 and the same total daily amount of amisulprideas the modified release pharmaceutical composition, wherein the value ofCmin is that at about 9 hours after administration; and/or

(11) the modified release composition used in treating the psychiatricdisorder is effective in minimizing the difference between Cmin and Cmaxof amisulpride compared to the immediate release composition having thecomposition of Table 25 and the same total daily amount of amisulprideas the modified release pharmaceutical composition, wherein the valuesof Cmax and Cmin are determined within about 9 hours afteradministration; and/or

(12) the modified release composition, when administered to a subjectpopulation, is effective in providing a ratio of Cmax/Cmin ofamisulpride that is less than about 2, less than about 1.9, or less thanabout 1.8, wherein the value of Cmin is that at about 9 hours afteradministration, where in various embodiments the values of Cmax and Cminare the population geometric mean values; and/or

(13) the modified release composition, when administered to a subjectpopulation, is effective in providing a population Cmax/Cmin ratio ofamisulpride that is less than about 2, less than about 1.9, or less thanabout 1.8, wherein the values of Cmax and Cmin are determined withinabout 9 hours after administration, where in various embodiments thevalues of Cmax and Cmin are the population geometric mean values; and/or

(14) when the modified release composition is administered to a subjectpopulation (i) the area under the curve (AUC) of blood plasmaconcentration versus time of amisulpride from administration to Tmax(AUC_(0-Tmax)) is less than about 19%, less than about 18%, less thanabout 17%, less than about 16%, less than about 15%, less than about14%, less than about 13%, or less than about 12% of the area under thecurve from administration to 48 hours (AUC₀₋₄₈); and (ii) Tmax ofamisulpride is between about 4 and about 6 hours after administration;and/or

(15) when the modified release composition is administered to a subjectpopulation (i) the area under the curve (AUC) of blood plasmaconcentration versus time of amisulpride from administration to Tmax(AUC_(0-Tmax)) is less than about 17%, less than about 16%, less thanabout 15%, less than about 14%, less than about 13%, or less than about12% of the area under the curve from administration to “infinity”(AUC_(0-INF)), and (ii) Tmax of amisulpride is between about 4 and about6 hours after administration; and/or

(16) the modified release composition when administered to a subjectpopulation provides a plasma concentration profile substantially thesame as the profile of Lot 4Z in FIG. 22B, Lot 4Z in FIG. 22F, Lot 3Z inFIG. 22C, Lot 3Z in FIG. 22H, Lot 3Z in FIG. 22J, Lot 3Z with subjectsin a fed state in FIG. 22I, Lot 3Z Fed State in FIG. 22D; and/or

(17) the modified release composition when administered to a subjectpopulation provides a plasma concentration profile substantially thesame as the profile of Lot 5Z in FIG. 22G, or Lot 6Z in FIG. 22K; and/or

(18) the modified release composition when administered to a subjectpopulation provides a blood plasma Cmax of amisulpride that is less thanabout 75%, 70%, 65%, 60%, 55%, or 50% of the Cmax achieved by theimmediate release composition described in Table 25 and having the sametotal daily amount of amisulpride as in the modified releasecomposition; and/or

(19) the modified release composition when administered to a subjectpopulation provides (i) when said administration is about 200 mg perday, provides a population geometric mean Cmax of (a) less than about350 ng/mL; (b) less than about 300 ng/mL; or (c) less than about 250ng/mL; and/or (ii) when said administration is about 400 mg per day, apopulation geometric mean Cmax of (a) less than about 500 ng/mL; (b)less than about 475 ng/mL; or (c) less than about 450 ng/mL; and/or

(20) the modified release composition comprises about 200 mg of totalamisulpride and when administered to a subject population results in amaximum QT interval prolongation over the time period of 12 hours afteradministration of: (a) less than about 10 milliseconds (ms); (b) lessthan about 9 milliseconds (ms); (c) less than about 8 milliseconds (ms);(d) less than about 7 milliseconds (ms); (e) less than about 6milliseconds (ms); or (f) less than about 5 milliseconds (ms); and/or

(21) the modified release composition comprises about 200 mg of totalamisulpride and when administered to a subject population provides a QTinterval prolongation at geometric mean Cmax that is: (a) less thanabout 10 milliseconds (ms); (b) less than about 9 milliseconds (ms); (c)less than about 8 milliseconds (ms); (d) less than about 7 milliseconds(ms); (e) less than about 6 milliseconds (ms); or (f) less than about 5milliseconds (ms).

In various embodiments, the disorder is one or more of a mood disorder,bipolar disorder (BPD), depression, bipolar depression, major depressivedisorder (MDD), as an adjunctive treatment of major depressive disorder,major depressive disorder with mixed features (MDD-MF), treatmentresistant depression (TRD), schizophrenia, negative symptoms ofschizophrenia, and schizoaffective disorder. In various embodiments, theprovided are medicaments and methods for treatment of major depressiveepisodes associated with bipolar I disorder.

Treatment Cycle

It is to be understood that the modified release compositions can beadministered over a treatment cycle as a single dosage unit form,comprising both (R)-amisulpride and the (S)-amisulpride enantiomers, inseparate modified release dosage unit forms comprising only one of theamisulpride enantiomers, or a combination thereof. For example, invarious embodiments, the (R)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and the (S)-amisulpride, or a pharmaceuticallyacceptable salt thereof, are given separately during a treatment cycle.

In addition, it is to be understood that the administration of an amountof amisulpride over a treatment cycle may be provided in a multipledosage regimen. For example, in various embodiments, a multiple dosageregimen comprises dosage with two or more modified release dosage unitforms substantially simultaneously; dosage with two or more modifiedrelease dosage unit forms sequentially; dosage with two or more modifiedrelease dosage unit forms within a period of time from one another, invarious embodiments within 4 to 48 hours from one another; andcombinations thereof.

For example, in various embodiments, the treatment cycle is two days,where the total S-enantiomer dosage amount is given once per treatmentcycle (to, for example, maintain D₂ occupancy at therapeutic levels) andthe total R-enantiomer dosage amount is given up to three times per day(e.g. up to six times per treatment cycle at roughly equally spacedintervals), in various embodiments in roughly equal dosage amounts perdose (to, for example, maintain desired plasma levels and have 5-HT7effects throughout the day).

In various embodiments, the treatment cycle is daily and theadministration occurs: (a) once per day; (b) twice per day; (c) thriceper day; or (d) four times per day. In various embodiments, thetreatment cycle is every two days.

In various embodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, of the ratio portion of the modified releasecompositions, over a treatment cycle is about 85:15 by weight of thefree base, the treatment cycle is daily and the total amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 200 mg over thetreatment cycle. In various embodiments, the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride over a treatment cycle isabout 85:15 by weight of the free base, the treatment cycle is daily andthe total amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about400 mg over the treatment cycle.

Polymorphs/Crystal Forms

It is to be understood, that in various embodiments that one or both ofthe enantiomeric amisulprides used in the various compositions,formulations, methods and medicaments is a crystalline form of the freebase of the enantiomeric amisulpride of crystalline Forms A and Form A′as described in FIGS. 11A-11C and 12A-12D. In various embodiments, the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal FormA; the (S)-(−)-amisulpride is crystalline (S)-(−)-amisulpride of crystalForm A′, or both.

In various embodiments the enantiomeric amisulpride is provided in oneor more of high polymorph purity, chiral purity, and chemical purity.

In various embodiments, the (R)-(+)-amisulpride is crystalline(R)-(+)-amisulpride of crystal Form A and has greater than about 95%chemical purity; the (S)-(−)-amisulpride is crystalline(S)-(−)-amisulpride of crystal Form A′ and has greater than about 95%chemical purity, or the (R)-(+)-amisulpride is crystalline(R)-(+)-amisulpride of crystal Form A having a greater than about 95%chemical purity and the (S)-(−)-amisulpride is crystalline(S)-(−)-amisulpride of crystal Form A′ having greater than about 95%chemical purity.

In various embodiments, crystalline forms of the present inventions haveseveral advantageous physical properties. For example, in contrast to(S)-amisulpride D-tartrate crystalline forms, the (R)-amisulpride Form Aand (S)-amisulpride Form A′ crystalline forms are substantiallynon-hygroscopic, exhibiting less than a 0.5% maximum mass change inwater sorption isotherms, at 25° C. scanned over 0 to 95% relativehumidity, as measured by dynamic vapor sorption (DVS), whereascrystalline (S)-amisulpride D-tartrate was found to be highlyhygroscopic, exhibiting a 52±9% (n=4, σ=18.25) maximum mass change inwater sorption isotherms, at 25° C. scanned over 0 to 95% relativehumidity, as measured by DVS.

The abbreviation “DSC” refers to differential scanning calorimetry, theabbreviation XRPD refers to x-ray powder diffraction, the abbreviationNMR refers to nuclear magnetic resonance, the abbreviation DVS refersto, dynamic vapor sorption, the abbreviation HPLC refers to highperformance liquid chromatography, and the abbreviation GC refers to gaschromatography. The abbreviations (R)-(+)-amisulpride and(R)-amisulpride refer toR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide.The abbreviations (S)-(−)-amisulpride and (S)-amisulpride refer toS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide.

As used herein the term “polymorph purity” refers to the weight % thatis the specified polymorph form. For example, when a crystalline(R)-amisulpride Form A is characterized as having greater than 95%polymorph purity, that means that greater than 95% by weight of thesubstance is crystalline (R)-amisulpride of Form A and less than 5% byweight of any other polymorph or amorphous form of (R)-amisulpride.

As used herein the terms “chiral purity” and “enantiomeric purity” areused interchangeably and refers to the weight % that is the specifiedenantiomer. For example, when a (R)-amisulpride containing substance(such as a compound or crystal) is characterized as having greater than90% chiral purity, that means that greater than 95% by weight of theamisulpride in the substance is the (R)-amisulpride and less than 5% byweight is in any other enantiomeric form of amisulpride.

As used herein the term “chemical purity” refers to the weight % that isthe specified chemical entity, including specified polymorph form. Forexample, when a crystalline amisulpride Form A is characterized ashaving greater than 95% chemical purity, that means that greater than95% by weight of the substance is crystalline amisulpride Form A andless than 5% by weight of other compound including other polymorphs.

For example, when a crystalline (R)-amisulpride Form A is characterizedas having greater than 99% chemical purity and greater than 97% chiralpurity, that means greater than 97% by weight of the substance is ofenantiomeric form (R)-amisulpride Form A and less than 3% by weight ofany other amisulpride enantiomer, and that greater than 99% by weight ofthe substance is amisulpride and less than 1% by weight of othercompounds. For example, when a crystalline (R)-amisulpride Form A ischaracterized as having greater than 99% chemical purity, greater than97% chiral purity and greater than 95% polymorph purity, that means thatgreater than 95% by weight of the substance is crystalline(R)-amisulpride of Form A and less than 5% by weight of any otherpolymorph or amorphous form of (R)-amisulpride, greater than 97% byweight of the substance is of enantiomeric form (R)-amisulpride and lessthan 3% by weight of any other amisulpride enantiomer, and that greaterthan 99% by weight of the substance is amisulpride and less than 1% byweight of other compounds.

Chemical purity may be characterized using a number of conventionalanalytical techniques, including but not limited to high performanceliquid chromatography (HPLC) and gas chromatography (GC). Chiral purity(also known as enantiomeric purity) may be characterized using a numberof conventional analytical techniques, including but not limited tochiral high performance liquid chromatography (HPLC). Water content maybe characterized using a number of conventional analytical techniques,including but not limited to coulometric titration.

For example, in various embodiments, crystalline (R)-amisulpride of FormA, crystalline (S)-amisulpride of Form A′, or both, are provided asactive ingredients that have a greater than about 90% polymorph purity,greater than about 95% polymorph purity, greater than about 97%polymorph purity, greater than about 99% polymorph purity, greater thanabout 99.5% polymorph purity, greater than about 99.7% polymorph purity,or greater than about 99.9% polymorph purity.

For example, in various embodiments, crystalline (R)-amisulpride of FormA, crystalline (S)-amisulpride of Form A′, or both, are provided asactive ingredients that have a greater than about 95% chemical purity,greater than about 97% chemical purity, greater than about 99% chemicalpurity, greater than about 99.5% chemical purity, greater than about99.7% chemical purity, or greater than about 99.9% chemical purity. Invarious embodiments, crystalline (R)-amisulpride of Form A, crystalline(S)-amisulpride of Form A′, or both, are provided that has less thanabout 8000 ppm residual solvents, less than about 6000 ppm residualsolvents, less than about 4000 ppm residual solvents, less than about2000 ppm residual solvents, less than about 1000 ppm residual solvents,less than about 800 ppm residual solvents, or less than about 500 ppmresidual solvents.

Disorders

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Ed.,hereinafter, the “DSM-5”), published by the American PsychiatricAssociation in 2013, and is incorporated herein by reference, provides astandard diagnostic system upon which persons of skill rely fordiagnosis of various diseases and disorders.

In various aspects, the disease or disorder which the medicaments andmethods treat comprises one or more of a psychiatric disorder; mooddisorder; depressive disorder; bipolar disorder; bipolar depression(e.g. major depressive episodes associated with bipolar I disorder),schizophrenia; schizoaffective disorder; anxiety disorder;obsessive-compulsive disorder; behavior disturbances associated with aneurocognitive disorder; conduct disorder; neurological disorder;medication-induced movement disorder; and motor disorder.

In various embodiments, the neurological or psychiatric disease ordisorder is one or more of a mood disorder, bipolar disorder (BPD),depression, bipolar depression, major depressive episodes associatedwith bipolar I disorder, major depressive disorder (MDD), as anadjunctive treatment of major depressive disorder, major depressivedisorder with mixed features (MDD-MF), treatment resistant depression(TRD), schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression (TRD) and schizoaffective disorder.

In various embodiments, the neurological or psychiatric disease ordisorder is selected from a psychosis, including schizophrenia(paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (e.g., phencyclidine, ketamine and other dissociativeanesthetics, amphetamine and other psychostimulants and cocaine)psychotic disorder, psychosis disorder, psychosis associated withaffective disorders, brief reactive psychosis, schizoaffectivepsychosis, “schizophrenia-spectrum” disorders such as schizoid orschizotypal personality disorders, or illnesses with associatedpsychosis (such as major depression, manic depressive (bipolar)disorder, Alzheimer's disease and post-traumatic stress syndrome),including both positive, negative, and cognitive symptoms ofschizophrenia and other psychoses; anxiety disorders including acutestress disorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder and related disorders including bodydysmorphic disorder, hoarding disorder, trichotillomania, andexcoriation disorder, panic attack, panic disorder, post-traumaticstress disorder, separation anxiety disorder, social phobia, specificphobia, substance-induced anxiety disorder and anxiety due to a generalmedical condition; substance-related disorders and addictive behaviors(including substance-induced delirium, persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder; tolerance,dependence or withdrawal from substances including alcohol,amphetamines, Cannabis, cocaine, hallucinogens, inhalants, nicotine,opioids, phencyclidine, sedatives, hypnotics or anxiolytics); eatingdisorders such as obesity, bulimia nervosa, pica and compulsive eatingdisorders; bipolar disorders, including, bipolar depression, bipolar Idisorder, bipolar II disorder, cyclothymic disorder,substance/medication-induced bipolar and related disorders, bipolar andrelated disorder due to another medical condition, other specifiedbipolar and related disorder, and unspecified bipolar and relateddisorders, depressive disorders including, but not limited to, unipolardepression, seasonal depression and post-partum depression, atypicaldepression, catatonic depression, elderly depression, endogenousdepression, melancholic depression, perinatal depression, situationaldepression, chronic depression, bipolar depression, major depressivedisorder (MDD), as an adjunctive treatment MDD, major depressivedisorder with anxious distress, MDD with mixed features (MDD-MF), MDDwith melancholic features, MDD with atypical features, MDD withmood-congruent psychotic features, MDD with mood-incongruent psychoticfeatures, MDD with catatonia, with peripartum onset, MDD with seasonalpattern, treatment resistant depression (TRD), and persistent depressivedisorder (dysthymia), and are associated with depressed mood (sadness),poor concentration, insomnia, fatigue, appetite disturbances, excessiveguilt and thoughts of suicide, premenstrual syndrome (PMS) andpremenstrual dysphoric disorder (PDD), mood disorders due to a generalmedical condition, and substance-induced mood disorders; and sleepdisorders including insomnia, disturbed sleep, jet lag, hypersomnia,cataplexy, sleep apnea, obstructive sleep apnea, REM sleep behaviordisorder, Restless Leg Syndrome, periodic limb movement disorder,circadian rhythm sleep disorders, delayed sleep phase disorder,sleepwalking, night terrors, bed wetting, rapid eye movement sleepbehavior disorder, shift work sleep disorder, excessive daytimesleepiness, non-24-hour sleep-wake disorder, sleep paralysis andnarcolepsy.

Psychiatric disorders are pathological conditions of the braincharacterized by identifiable symptoms that result in abnormalities incognition, emotion or mood, or the highest integrative aspects ofbehavior. These disorders may vary in severity of symptoms, duration,and functional impairment. Psychiatric disorders afflict millions ofpeople worldwide resulting in tremendous human suffering and economicburden due to lost productivity. Mood disorders are a type ofpsychiatric disorder often defined as a group of heterogeneous,typically recurrent illnesses including unipolar (depressive) andbipolar (manic-depressive) disorders characterized by pervasive mooddisturbances, psychomotor dysfunction, and vegetative symptoms. Suicide,the most serious complication in patients with mood disorders, is thecause of death in 15 to 25% of untreated patients with mood disorders;unrecognized or inadequately treated depression contributes to 50 to 70%of all completed suicides.

The term “mood disorder” as used herein includes depression, majordepression, major depressive disorder, mild depression, severedepression without psychosis, severe depression with psychosis,melancholia (formerly endogenous depression), atypical depression,dysthymic disorder, manic depression, bipolar disorder, bipolardepression (e.g. major depressive episodes associated with bipolar Idisorder), bipolar I disorder, bipolar II disorder, bipolar IIIdisorder, cyclothymic disorder, and chronic hypomania.

In various embodiments, the neurological or psychiatric disease ordisorder is a bipolar disorder. Bipolar disorders (including bothbipolar I and bipolar II) are serious psychiatric disorders that have aprevalence of approximately 2% of the population, and affects bothgenders alike. It is a relapsing-remitting condition characterized bycycling between elevated (i.e., manic) and depressed moods, whichdistinguishes it from other disorders such as major depressive disorderand schizophrenia. Bipolar I is defined by the occurrence of a fullmanic episode, although most individuals experience significantdepression. Symptoms of mania include elevated or irritable mood,hyperactivity, grandiosity, decreased need for sleep, racing thoughtsand in some cases, psychosis. The depressive episodes are characterizedby anhedonia, sad mood, hopelessness, poor self-esteem, diminishedconcentration and lethargy. Bipolar II is defined as the occurrence of amajor depressive episode and hypomanic (less severe mania) episodealthough patients spend considerable more time in the depressive state.Other related conditions include cyclothymic disorder.

In bipolar I disorder, full-fledged manic and major depressive episodesalternate. Bipolar I disorder commonly begins with depression and ischaracterized by at least one manic or excited period during its course.The depressive phase can be an immediate prelude or aftermath of mania,or depression and mania can be separated by months or years.

In bipolar II disorder, depressive episodes alternate with hypomanias(relatively mild, nonpsychotic periods of usually <1 week). During thehypomanic period, mood brightens, the need for sleep decreases, andpsychomotor activity accelerates beyond the patient's usual level.Often, the switch is induced by circadian factors (e.g., going to beddepressed and waking early in the morning in a hypomanic state).Hypersomnia and overeating are characteristic and may recur seasonally(e.g., in autumn or winter); insomnia and poor appetite occur during thedepressive phase. For some persons, hypomanic periods are adaptivebecause they are associated with high energy, confidence, andsupernormal social functioning. Many patients who experience pleasantelevation of mood, usually at the end of a depression, do not report itunless specifically questioned.

Patients with major depressive episodes and a family history of bipolardisorders often exhibit subtle hypomanic tendencies; their temperamentis termed hyperthymic (i.e., driven, ambitious, andachievement-oriented).

In cyclothymic disorder, less severe hypomanic and mini-depressiveperiods follow an irregular course, with each period lasting a few days.Cyclothymic disorder is commonly a precursor of bipolar II disorder. Butit can also occur as extreme moodiness without being complicated bymajor mood disorders. In such cases, brief cycles of retarded depressionaccompanied by low self-confidence and increased sleep alternate withelation or increased enthusiasm and shortened sleep. In another form,low-grade depressive features predominate; the bipolar tendency is shownprimarily by how easily elation or irritability is induced byantidepressants. In chronic hypomania, a form rarely seen clinically,elated periods predominate, with habitual reduction of sleep to <6hours. Persons with this form are constantly overcheerful, self-assured,overenergetic, full of plans, improvident, overinvolved, and meddlesome;they rush off with restless impulses and accost people.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of bipolar I disorder, bipolar IIdisorder, cyclothymic disorder, other specified bipolar and relateddisorder, or unspecified bipolar and related disorder, and bipolar Idisorder or bipolar II disorder with the specifiers of anxious distress,with mixed features, with rapid cycling, with melancholic features, withatypical features, with mood-congruent psychotic features, with moodincongruent psychotic features, with catatonia, with peripartum onset,and/or with seasonal pattern. A relatively recent article by Hu et al[Prim Care Companion CNS Disord. 2014; 16(2): PCC.13r01599] highlightsthat bipolar disorder, while commonly encountered in the primary caresetting, is often misdiagnosed or undiagnosed. The DSM-5 attempts tocapture the large proportion of patients with subsyndromal mixedsymptoms with the inclusion of the mixed specifier.

In various embodiments, the neurological or psychiatric disease ordisorder is a depressive disorder. Depressive disorders include, but arenot limited to, depressive disorders including, but not limited to,unipolar depression, seasonal depression and post-partum depression,atypical depression, catatonic depression, elderly depression,endogenous depression, melancholic depression, perinatal depression,situational depression, chronic depression, bipolar depression (e.g.,major depressive episodes associated with bipolar I disorder), majordepressive disorder (MDD), major depressive disorder with mixed features(MDD-MF), treatment resistant depression (TRD), and dysthymia, and areassociated with depressed mood (sadness), poor concentration, insomnia,fatigue, appetite disturbances, excessive guilt and thoughts of suicide,premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD),mood disorders due to a general medical condition, and substance-inducedmood disorders.

Depression is an affective disorder, the pathogenesis of which cannot beexplained by any single cause or theory. Unfortunately, treatmentoptions for depressed patients who have suboptimal clinical responses totherapy with an antidepressant are limited. Approximately thirty percent(30%) of patients initiating antidepressant therapy show suboptimal ordelayed clinical responses to the first-line antidepressant agents thatare commonly used to treat depression.

Typically, if a patient exhibits suboptimal or delayed clinical responseafter several weeks of therapy with an antidepressant, the clinician'sinitial approach is to increase the dose of the antidepressant. If thepatient's response remains unsatisfactory after increasing the dose, themost common approaches that many clinicians will pursue are: a)switching to another antidepressant; or b) adding a secondantidepressant; or c) attempting an augmentation therapy byadministering agents such as lithium carbonate, thyroid hormone(triiodothyronine), psychostimulants, modafinil, atypicalantipsychotics, buspirone, or pindolol.

In its full syndromal expression, clinical depression manifests as majordepressive disorder, with episodic course and varying degrees ofresidual manifestations between episodes. The mood is typicallydepressed, irritable, and/or anxious. The patient may appear miserable,with furrowed brows, downturned corners of the mouth, slumped posture,poor eye contact, and monosyllabic (or absent) speech. The morbid moodmay be accompanied by preoccupation with guilt, self-denigrating ideas,decreased ability to concentrate, indecisiveness, diminished interest inusual activities, social withdrawal, helplessness, hopelessness, andrecurrent thoughts of death and suicide. Sleep disorders are common. Insome, the morbid mood is so deep that tears dry up; the patientcomplains of an inability to experience usual emotions—including grief,joy, and pleasure—and of a feeling that the world has become colorless,lifeless, and dead.

Melancholia (formerly endogenous depression) is characterized by markedpsychomotor slowing (of thinking and activity) or agitation (e.g.,restlessness, wringing of the hands, pressure of speech), weight loss,irrational guilt, and loss of the capacity to experience pleasure. Moodand activity vary diurnally, with a nadir in the morning. Mostmelancholic patients complain of difficulty falling asleep, multiplearousals, and insomnia in the middle of the night or early morning.Sexual desire is often diminished or lost. Amenorrhea can occur.Anorexia and weight loss may lead to emaciation and secondarydisturbances in electrolyte balance.

In atypical depression, reverse vegetative features dominate theclinical presentation; they include anxious-phobic symptoms, eveningworsening, initial insomnia, hypersomnia that often extends into theday, and hyperphagia with weight gain. Unlike patients with melancholia,those with atypical depression show mood brightening to potentiallypositive events but often crash into a paralyzing depression with theslightest adversity. Atypical depressive and bipolar II disordersoverlap considerably.

In dysthymic disorder, depressive symptoms typically begin insidiouslyin childhood or adolescence and pursue an intermittent or low-gradecourse over many years or decades; major depressive episodes maycomplicate it (double depression). In pure dysthymia, depressivemanifestations occur at a subthreshold level and overlap considerablywith those of a depressive temperament: habitually gloomy, pessimistic,humorless, or incapable of fun; passive and lethargic; introverted;skeptical, hypercritical, or complaining; self-critical,self-reproaching, and self-derogatory; and preoccupied with inadequacy,failure, and negative events.

Thorough evaluation of many persons with depression reveals bipolartraits, and as many as one in five patients with a depressive disorderalso develops frank hypomania or mania. Most switches from unipolar tobipolar disorder occur within 5 years of the onset of depressivemanifestations. Predictors of a switch include early onset of depression(<25 years old), postpartum depression, frequent episodes of depression,quick brightening of mood with somatic treatments (e.g.,antidepressants, phototherapy, sleep deprivation, electroconvulsivetherapy), and a family history of mood disorders for three consecutivegenerations.

Between episodes, patients with bipolar disorder exhibit depressivemoodiness and sometimes high-energy activity; disruption indevelopmental and social functioning in bipolar depression is morecommon than in unipolar disorder. In bipolar disorder, depressionepisodes are shorter (3 to 6 months), age of onset is younger, onset ofepisodes is more abrupt, and cycles (time from onset of one episode tothat of the next) are shorter than in unipolar disorder. Cyclicity isparticularly accentuated in rapid-cycling forms of bipolar disorder(usually defined as >=4 episodes/year). In addition depressive episodesin bipolar disorder are a difficult component of BPD to treat. Forexample, psychiatrists indicate that about 25% of patients across allbipolar disorders are refractory during a manic episode, while about 70%are refractory during a depressive episode.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of bipolar depression, majordepressive episodes associated with bipolar I disorder, major depressivedisorder (MDD), persistent depressive disorder (Dysthymia), premenstrualdysphoric disorder (PMDD), major depressive disorder with mixed features(MDD-MF), depressive disorder due to another medical condition, otherspecified depressive disorder, unspecified depressive disorder, ortreatment resistant depression (TRD), and MDD with the specifiers ofanxious distress, with mixed features, with melancholic features, withatypical features, with mood-congruent psychotic features, withmood-incongruent psychotic features, with catatonia, with peripartumonset, and/or with seasonal pattern, and seasonal affective disorder.

It is to be understood that TRD is a term used in clinical psychiatry todescribe cases of major depressive disorder (MDD) that do not respondadequately to appropriate courses of adequate dose and duration of atleast two antidepressants.

In various embodiments, a depressive disorder is associated with acutesuicidality or suicide ideation. The United States Food and DrugAdministration has adopted a “black box” label warning indicating thatantidepressants may increase the risk of suicidal thinking and behaviorin some children, adolescents and young adults (up to age 24) with adepressive disorder such as MDD. In various embodiments, it is believedthat the compositions and methods of the present inventions do notincrease the risk of suicidal thinking and/or behavior in children,adolescents and/or young adults with a depressive disorder, e.g., withMDD. In various embodiments, the present inventions provide medicamentsfor and provide methods of treating one or more symptoms of a depressivedisorder (e.g., MDD) in children, adolescents and/or young adultswithout increasing the risk of suicidal thinking and/or behavior.

In various embodiments, the neurological or psychiatric disease ordisorder is schizophrenia. Schizophrenia is a disorder of unknownorigin, which usually appears for the first time in early adulthood andis marked by characteristics such as psychotic symptoms, phasicprogression and development, and/or deterioration in social behavior andprofessional capability. Characteristic psychotic symptoms are disordersof thought content (e.g., multiple, fragmentary, incoherent, implausibleor simply delusional contents, or ideas of persecution) and of mentality(e.g., loss of association, flight of imagination, incoherence up toincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and/or inter-humanrelationships, and psychomotoric disorders (e.g., catatonia). Othersymptoms are also associated with this disorder. Schizophrenia isclassified into subgroups: the paranoid type, characterized by delusionsand hallucinations and absence of thought disorder, disorganizedbehavior, and affective flattening; the disorganized type, also named“hebephrenic schizophrenia,” in which thought disorder and flat affectare present together; the catatonic type, in which prominent psychomotordisturbances are evident, and symptoms may include catatonic stupor andwaxy flexibility; and the undifferentiated type, in which psychoticsymptoms are present but the criteria for paranoid, disorganized, orcatatonic types have not been met. The symptoms of schizophrenianormally manifest themselves in three broad categories: positive,negative and cognitive symptoms. Positive symptoms are those whichrepresent an “excess” of normal experiences, such as hallucinations anddelusions. Negative symptoms are those where the patient suffers from alack of normal experiences, such as anhedonia and lack of socialinteraction. The cognitive symptoms relate to cognitive impairment inschizophrenics, such as lack of sustained attention and deficits indecision making.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of schizotypal (personality)disorder, delusional disorder, brief psychotic disorder,schizophreniform disorder, schizophrenia, schizoaffective disorder,substance/medication-induced psychotic disorder, psychotic disorder dueto another medical condition, other specified schizophrenia spectrum andother psychotic disorder, unspecified schizophrenia spectrum, and otherpsychotic disorder.

It is to be understood that schizoaffective disorder includes acondition that includes aspects of both schizophrenia and a mooddisorder, such as, for example, a major depressive disorder, a bipolardisorder, major depressive episodes associated with a bipolar disorder,etc.

In various embodiments, the neurological or psychiatric disease ordisorder is anxiety disorder. Anxiety disorders are characterized byfear, worry, and uneasiness, usually generalized and unfocused as anoverreaction to a situation. Anxiety disorders differ in the situationsor types of objects that induce fear, anxiety, or avoidance behavior,and the associated cognitive ideation. Anxiety differs from fear in thatanxiety is an emotional response to a perceived future threat while fearis associated with a perceived or real immediate threat. They alsodiffer in the content of the associated thoughts or beliefs. Examples ofanxiety disorders include separation anxiety disorder, selective mutism,specific phobia, social anxiety disorder (social phobia), panicdisorder, panic attack specifier, agoraphobia, generalized anxietydisorder, substance/medication-induced anxiety disorder, anxietydisorder due to another medical condition, illness anxiety disorder,social (pragmatic) communication disorder, other specified anxietydisorder, and unspecified anxiety disorder; stressor-related disorders,including reactive attachment disorder, disinhibited social engagementdisorder, posttraumatic stress disorder (PTSD), acute stress disorder,and adjustment disorders.

In various embodiments, the neurological or psychiatric disease ordisorder is a sleep disorder including those sleep disorders which areproduced by psychiatric conditions, including, but not limited to,insomnia, disturbed sleep, jet lag, hypersomnia, cataplexy, sleeprelated disorder (e.g., sleep apnea, insomnia, narcolepsy, cataplexy),obstructive sleep apnea, REM sleep behavior disorder, Restless LegSyndrome, periodic limb movement disorder, circadian rhythm sleepdisorders, delayed sleep phase disorder, sleepwalking, night terrors,bed wetting, rapid eye movement sleep behavior disorder, shift worksleep disorder, excessive daytime sleepiness, non-24-hour sleep-wakedisorder, sleep paralysis and narcolepsy.

In various embodiments, the present inventions provide medicaments forand provide methods of suppressing rapid eye movement (REM) during bothsleep and daytime equivalent.

In various embodiments, the present inventions provide medicaments forand provide methods of suppressing or eliminating pathological orexcessive REM during the night or daytime equivalent.

In various embodiments, the neurological and/or psychiatric disease ordisorders are obsessive-compulsive disorder and related disorders (e.g.,body dysmorphic disorder, hoarding disorder, trichotillomania,excoriation disorder).

In various embodiments, the neurological and/or psychiatric diseases ordisorders are disruptive, impulse-control, and conduct disordersincluding oppositional defiant disorder, intermittent explosivedisorder, conduct disorder, antisocial personality disorder, pyromania,kleptomania, other specified disruptive, impulse-control, and conductdisorder, unspecified disruptive, impulse-control, and conduct disorder.

In various embodiments, the compositions, formulations, methods andmedicaments may be used in combination with other therapies. Suitabletherapies include, but are not limited to, psychotherapy, cognitivebehavioral therapy, electroconvulsive therapy, transcranial magneticstimulation, vagus nerve stimulation, and deep-brain stimulation.

Aspects, embodiments, and features may be further understood from thefollowing examples, which should not be construed as limiting the scopeof the inventions. Example 1 presents in vitro data, Examples 2 and 3animal study data, and Examples 4-7 present human clinical data.

Example 1: In Vitro Assays of Dopamine D2 and Serotonin 5-HT7 Affinities

Amisulpride enantiomers and racemic amisulpride were tested for affinityto Dopamine D₂s receptors recombinantly expressed in human ChineseHamster Ovary (CHO) cells by radioligand binding techniques (EurofinsPanlabs, Inc.). The receptors' B_(max) value was 1.6 pmole/mg protein.The radioligand was [3H] Spiperone at 0.16 nM concentration with 0.090nM dissociation constant (Kd, historical value under identicallaboratory conditions). The incubation buffer was 50 mM Tris-HCl, pH7.4, 1.4 mM ascorbic acid, 0.001% BSA, and 150 mM NaCl. The amisulpridecompound under study (e.g., enantiomeric amisulprides and racemicamisulpride) was dissolved in dimethyl sulfoxide (DMSO) and added to theassay wells for a 1% final concentration. Percent inhibition values ofspecific binding by amisulpride enantiomers and racemic amisulpride weregenerated with 12 serial dilutions from 10 micromolar down to 3 nM finalconcentrations. Each concentration was tested in duplicate. Amisulprideenantiomer affinities and racemic amisulpride affinities for dopamine D2receptors are based on the average of 3 independent experiments.Affinities were calculated with the Cheng-Prusoff equation and theobserved IC50 of the tested compound, the concentration of radioligandemployed in the assay, and the historical value for the Kd of the ligand(obtained experimentally).

Amisulpride enantiomers and racemic amisulpride were tested for affinityto Serotonin 5-HT₇ receptors recombinantly expressed in human CHO-K1cells by radioligand binding techniques (Eurofins Panlabs, Inc.). Thereceptors' B_(max) value was 0.95 pmole/mg protein. The radioligand is[3H]Lysergic acid diethylamide (LSD) at 5.5 nM concentration with 7.40nM dissociation constant (Kd, historical value under identicallaboratory conditions). The incubation buffer was 50 mM Tris-HCl, pH7.4, 10 mM MgCl₂, 0.5 mM EDTA. The amisulpride compound under study(e.g., enantiomeric amisulprides and racemic amisulpride) was dissolvedin DMSO and added to the assay wells for a 1% final concentration.Percent inhibition values of specific binding by amisulpride enantiomersand racemic amisulpride were generated with 12 serial dilutions from 10micromolar down to 3 nM final concentrations. Each concentration wastested in duplicate. Amisulpride enantiomer affinities and racemicamisulpride affinities for serotonin 5-HT7 receptors are based on theaverage of 3 independent experiments. Affinities were calculated withthe Cheng-Prusoff equation and the observed IC50 of the tested compound,the concentration of radioligand employed in the assay, and thehistorical value for the Kd of the ligand (obtained experimentally).

Percent inhibition of specific binding was determined as a function oftest drug concentration (i.e., (R)-amisulpride (S)-amisulpride, andracemic amisulpride). It was discovered that there are distinctpharmacological activities with the potential for combined clinicalbenefit which reside in opposite enantiomers.

Referring to FIG. 5A, depicted is the data on the % inhibition ofdopamine D2 binding of Example 1 for (R)-amisulpride (downwardtriangle), (S)-amisulpride (upward triangle), and racemic amisulpride(circle). The vertical bars represent ±1 standard deviation from the 3independent determinations. FIG. 5A illustrates that the (S)-enantiomeris the more potent enantiomer for dopamine D₂ receptors.

Referring to FIG. 5B, depicted is the data on the % inhibition ofserotonin 5-HT7 binding of Example 1 for (R)-amisulpride (downwardtriangle), (S)-amisulpride (upward triangle), and racemic amisulpride(circle). The vertical bars represent ±1 standard deviation from the 3independent determinations. FIG. 5B illustrates that the (R)-enantiomeris more potent in inhibiting binding to serotonin 5-HT₇ receptors.

Table 19 summarizes inhibitor constant (Ki) values in nM determined invitro by radioligand binding and compares racemic amisulpride to amixture of of (R)-(+)-amisulpride and (S)-(−)-amisulpride of about 85:15by weight. Human dopamine D₂ receptors or human serotonin 5-HT₇receptors were expressed in CHO cells or CHO-K1 cells, respectively.Standard error of the mean is presented based on multiple, independentdeterminations.

TABLE 19 (R)-amisulpride:(S)-amisulpride Racemic (50:50) (85:15)Dopamine D₂  7.1 ± 0.26   17 ± 0.62 Serotonin 5-HT₇ 89 ± 2  66 ± 165-HT₇/D₂ 13 4

Example 1 shows that the (R)-enantiomer is highly stereoselective forserotonin 5-HT7 receptors such that the 5-HT7 antagonism of amisulprideresides almost exclusively in the (R)-enantiomer and that the(S)-enantiomer is highly stereoselective for dopamine D2 receptors suchthat the D2 antagonism of racemic amisulpride resides predominantly inthe (S)-enantiomer. Referring to again to FIG. 5A, the D2 antagonism of(S)-amisulpride was determined to be about 20 fold that of the(R)-amisulpride, and referring to again to FIG. 5B, the 5-HT7 antagonismof (R)-amisulpride was determined to be about 300 fold that of the(S)-amisulpride.

Referring to FIG. 5C, depicted is the data on relative receptor affinity(5-HT7: D2) for various mixtures of (R)-amisulpride and (S)-amisulpride,determined in accordance with the procedures of Example 1, where thex-axis indicates the percentage of the tested drug that was(R)-amisulpride, the remainder percentage being (S)-amisulpride. Table20 lists for various weight ratios (R)-amisulpride to (S)-amisulpride(first column), from the (S)-enantiomer alone (0:100 ratio) to(R)-enantiomer alone (100:0 ratio), the Ki values (average±1 standarddeviation) in nM for n=3 independent determinations, for dopamine D2(second column) and serotonin 5-HT7 (third column), and the ratio of5-HT7 to D2 Ki values (fourth column and plotted in FIG. 5C).

TABLE 20 Ki Values for Enantiomeric Amisulpride and Mixtures ofAmisulpride Enantiomers in vitro Ki values Ratio Ratio D2 Ki 5-HT7 5-HT7R:S (nM) (nM) D2  0:100 4.43 ± 0.70 1,860 ± 260  420 50:50 7.10 ± 0.2689 ± 2 13 60:40 7.51 ± 0.57 79 ± 4 11 65:35 6.50 ± 0.64 79 ± 9 12 70:308.54 ± 1.61 72 ± 4 8 75:25 8.16 ± 0.17 59 ± 6 7 80:20   12 ± 0.73  59 ±10 5 85:15   16 ± 0.62  66 ± 16 4 90:10 18.9 ± 0.95 48 ± 8 3 100:0  140± 31  47 ± 4 0.3

Examples 2, 3A, and 3B: Animal Studies

A series of animal studies were performed on rats with various doses of(R)-amisulpride.

Example 2: Forced Swim Test

The Forced Swim test (FST) is an indicator of the antidepressant-likeactivity of a test compound. The rat will swim before “giving up” andbecoming immobile. A compound with antidepressant-like activity willdecrease the time the rat is immobile.

The animals (n=90) were divided into five groups. Animals in four groupswere treated with one of the three doses of (R)-amisulpride orimipramine (control), whereas those in the other group received onlyvehicle (M phosphoric acid+0.1 M NaOH (pH6-7)). In the training session,each animal was gently placed into the plastic cylinder containing 5.8 Lof water set at 25±1° C. Fifteen minutes after the beginning of thetraining session, the animal was removed from the water. The dosingsolutions were administered 15 minutes after finishing of the training.

Prior to the swim test, animals were intraperitoneally administeredvehicle (1 ml/kg), imipramine (10 mg/kg) or (R)-amisulpride (0.15, 0.5and 1.5 mg/kg) at 24 hours, 5 hours and 1 hour prior to the swim test.The swim test was performed for 5 minutes in the same manner as thetraining session. In the swim test, the behavior of each animal washorizontally recorded using a video camera. After the swim test, animalswere immediately sacrificed by inhalation of carbon dioxide.

The swim movies were handled in a blind manner to ensure that the personwho measured the immobility time had no information on the treatment. Ananimal was judged to be immobile whenever it remained floating in thewater without moving its body or forepaws except for the slight movementto maintain its posture. The total time for which the animal remainedimmobile was defined as the immobility time. An observer blinded to thedoses measured the immobility times. The immobility time of each animalwas measured to one decimal place and rounded to a whole number.Immobility time was expressed in units of seconds. In each series themeans of immobility time were calculated and rounded to a whole numberusing. The mean and standard error (SE) for each group were calculatedusing the data obtained from three experimental series and rounded to awhole number. All results are represented as the mean±SE.

The data of imipramine were analyzed using t-test with a two-sidedsignificance level of 5% (p<0.05). In the case imipramine significantlydecrease the immobility time compared to control, the data of(R)-amisulpride were then analyzed parametrically using Dunnett'smultiple comparison test with a two-sided significance level of 5%(p<0.05). The data is presented in FIG. 6.

Referring to FIG. 6, data is presented for vehicle, imipramine(comparator), and 0.15, 0.5 and 1.5 mg/kg of (R)-amisulpride. Theimmobility time values are mean±standard error of the mean (SEM). Thesymbol ## indicates a p-value of p<0.01 vs. vehicle (determined using atwo-sided t-test); * indicates a p-value of p<0.05 and ** indicates ap-value of p<0.01 vs. vehicle (determined using a parametric two-sidedDunnett's multiple comparison test).

The immobility time of animals in the vehicle-treated group was 168±12sec. Imipramine of 10 mg/kg shortened the immobility time by more than20% in all series and the immobility time average was 105±15 sec, whichwas significantly shorter than the average of vehicle-treated group.Animals treated with (R)-amisulpride at doses of 0.15, 0.5, and 1.5mg/kg had immobility times of 142±11, 124±12 and 111±16 sec,respectively. (R)-amisulpride significantly decreased the immobilitytime at 0.5 and 1.5 mg/kg comparable to imipramine) indicative ofantidepressant-like activity for (R)-amisulpride.

Example 3A: Sleep Study of (R)-Amisulpride

In rodents, 5-HT7 receptor blockade has been shown to be effective inmodels of depression and to increase the latency to REM sleep anddecrease REM duration.

In this study, the effect of (R)-amisulpride on sleep architecture infreely moving rats in the light phase was evaluated. Rapid eye movement(REM) sleep time, non-rapid eye movement (NREM) sleep time, WAKE timewere measured using electroencephalogram (EEG) and electromyogram (EMG)recordings. (R)-amisulpride (10, 30, 100 mg/kg, p.o.) was administered10 min before the beginning of recording, during the light phase. EEGand EMG recordings were made for 6 hr starting at the beginning of thelight phase. Vehicle (0.05 N HCl/0.5% Methyl Cellulose 400 solution) ordosing suspensions were orally administered 10 min before the beginningof light phase. The volume of administration was 5 mL/kg. The order ofdrug treatment varied pseudo-randomly and at least 1 week was allowedbetween the experiments for individual animals.

A radio transmitter (TL11M2-F40-EET; Data Science International, NewBrighton, Minn., USA) was implanted subcutaneously in the back ofanesthetized animals, and a pair of electrode wires was stereotaxicallyimplanted into the skull in the following locations: one in thefrontoparietal (2 mm anterior to the bregma and 2 mm left to themidline), and the other in parietal (5 mm posterior to the bregma and 2mm right to the midline) areas. The EEG electrodes were fixed usingdental cement. Electromyograms (EMG) were recorded from the dorsal neckmuscle. The animals, then, were allowed at least 1 week recovery inindividual plastic cages before EEG/EMG recording. EEG/EMG were recordedin the home cages in a soundproof box using Dataquest A.R.T. software(Data Science International, New Brighton, Minn., USA) at a samplingrate of 500 Hz.

Sleep stage analysis was conducted off-line using Sleepsign software(KISSEI COMTEC CO., LTD, Nagano, Japan). Electrographic activity of10-sec epochs were analyzed and each epoch was automatically assigned asWAKE, REM, and NREM based on the waveforms of EEG and EMG according tothe following definitions: WAKE was defined as a condition in which EMGexceeded the individual threshold, NREM was defined as a condition inwhich the power of delta waves (0.5-4 Hz) exceeded the individualthreshold with no EMG activity, and REM was defined as a condition inwhich the power of theta waves (4-8 Hz) exceeded 40% of the total powerof frequencies between 0.5 and 80 Hz in the presence of no EMG activity.The duration of each REM, WAKE, and NREM periods were calculated bysumming time spent in each condition during sleep every 2 hours.

Referring to FIGS. 7A (n=6) and 7B (n=7), data is presented for vehicleand 10 mg/kg, 30 mg/kg and 100 mg/kg of (R)-amisulpride. The y-axisrepresents the time in minutes that REM sleep was suppressed and thesevalues are mean±standard error of the mean (SEM). The symbol * indicatesa p-value of p<0.05, ** indicates a p-value of p<0.01; and *** indicatesa p-value of p<0.001; (determined using a two-way ANOVA followed bypost-hoc parametric Dunnett multiple comparison test).

All data are expressed as means±S.E.M. REM sleep, NREM sleep time, andWAKE time each of sequential 2-hr periods were compared statisticallyusing a repeated measures two-way ANOVA, followed by post-hoc Dunnetttests. All statistical analyses were performed using GraphPad Prism 6software (GraphPad Software, Inc., CA, USA, ver. 6.03J).

It was determined that (R)-amisulpride (10, 30, 100 mg/kg, p.o.)treatment reduced REM sleep duration in dose-dependent manner in freelymoving rat, with significant reductions in REM sleep duration following100 mg/kg in the 0-2 hr and 2-4 hr periods (time after administration).There was no observed effect of (R)-amisulpride on NREM sleep time andWAKE time.

Example 3B: Sleep Study of 85:15 (R:S-Amisulpride) and RacemicAmisulpride

In rodents, 5-HT7 receptor blockade has been shown to be effective inmodels of depression and to increase the latency to REM sleep anddecrease REM duration.

In this study, the effect of 85:15 (R:S-amisulpride) and racemicamisulpride on sleep architecture in freely moving rats in the lightphase was evaluated. Groups in this study were as follows. Test compoundwas administered to rats in a cross-over design.

Fixed ratio Total dose (R/S dose) Number of Group No. amisulpride(mg/kg) animals 1 Vehicle (*) 2 R/S = 50/50  30 (15/15) 3 R/S = 85/15  30 (25.5/4.5) 4 R/S = 50/50 100 (50/50) 5 R/S = 85/15 100 (85/15) (*)0.05N HCl/0.5% MC treatment

Vehicle or fixed ratio amisulpride dosing solutions were orallyadministered 10 min before the beginning of light phase (light phase:10:00 AM to 10:00 PM). The individual dosing volume was 4 mL/kg. Theindividual dosing volume was calculated based on the animals' bodyweight measured on each experimental day. At least 1-week wash-outperiod after each treatment was provided.

Animal Treatments (R/S ratio; Dose mg/kg) No. 1^(st) 2^(nd) 3^(rd)4^(th) 5^(th) Rat 1 Vehicle 50/50; 100 85/15; 100 50/50; 30 85/15; 30Rat 2 50/50; 100 Vehicle 85/15; 100 50/50; 30 85/15; 30 Rat 3 Vehicle50/50; 100 85/15; 100 50/50; 30 85/15; 30 Rat 4 50/50; 100 Vehicle85/15; 100 50/50; 30 85/15; 30 Rat 5 Vehicle 50/50; 100 85/15; 10050/50; 30 85/15; 30 Rat 6 Vehicle 50/50; 100 85/15; 100 50/50; 30 85/15;30 Rat 7 50/50; 100 Vehicle 85/15; 100 50/50; 30 85/15; 30

The R-amisulpride and S-amisulpride were separately weighed. The vehicle(0.05 N HCl/0.5% MC solution) was then added to prepare each solutionwith a concentration of 25 mg/mL (100 mg/kg dosing solution) or 7.5mg/mL (30 mg/kg dosing solution). Fixed-ratio amisulpride (R/S=85/15 or50/50) solution (i.e. a dosing formulation) was prepared by mixingR-amisulpride and S-amisulpride solution.

A radio transmitter was implanted intraperitoneally in each anesthetizedanimal (sodium pentobarbital, 32.4 mg/kg, i.p. and medetomidinehydrochloride, 0.5 mg/kg, i.p.). A pair of electrode wires wasstereotaxically implanted into the skull in the following locations: onein the frontoparietal (2 mm anterior to the bregma and 2 mm left to themidline), and the other in parietal (5 mm posterior to the bregma and 2mm right to the midline) areas. The electroencephalogram (EEG)electrodes were fixed using dental cement. Electromyograms (EMG) wererecorded from the dorsal neck muscle. The animals were allowed at least2 weeks recovery in individual plastic cages before EEG/EMG recording.EEG/EMG was recorded in the home cages in a soundproof box usingDataquest A.R.T. software (Data Science International, New Brighton,Minn., USA) at a sampling rate of 500 Hz.

Sleep stage analysis was conducted off-line using Sleepsign software(KISSEI COMTEC CO., LTD, Japan). Electrographic activity of 10-secepochs were analyzed and each epoch was automatically assigned as WAKE,REM, and NREM based on the waveforms of EEG and EMG according to thefollowing definitions: WAKE was defined as a condition in which EMGexceeded the individual threshold, NREM was defined as a condition inwhich the power of delta waves (0.5-4 Hz) exceeded the individualthreshold with no EMG activity, and REM was defined as a condition inwhich the power of theta waves (4-8 Hz) exceeded 40% of the total powerof frequencies between 0.5 and 80 Hz in the presence of no EMG activity.Based on the previous study which demonstrated that R-amisulpride wasactive 0 to 4 hours after administration (1), durations of REM sleep,NREM sleep, and WAKE were calculated using the data from the first 4hours after treatment.

All data were expressed as a mean±SEM. Difference between 85/15 and50/50 amisulpride at each dose in each sleep architecture (i.e. REMsleep duration, NREM sleep duration, and WAKE duration) during the first4 hours after administration were assessed by a repeated measuresone-way ANOVA, followed by post-hoc Bonferroni multiple comparison test.All statistical analyses were performed using GraphPad Prism 6 software(GraphPad Software, Inc., CA, USA, ver. 6.03J). P values less than 0.05were considered to be statistically significant.

FIG. 7C presents data comparing vehicle to 30 mg/kg and 100 mg/kg of85:15 ratio (R:S-amisulpride) and racemic amisulpride in REM sleep time(min). FIG. 7D presents data comparing vehicle to 30 mg/kg and 100 mg/kgof 85:15 ratio (R:S-amisulpride) and racemic amisulpride in NREM sleeptime (min). FIG. 7E presents data comparing vehicle to 30 mg/kg and 100mg/kg of 85:15 ratio (R:S-amisulpride) and racemic amisulpride in WAKEtime (min).

Results show that at total 30 mg/kg dose of amisulpride, the fixed ratio(R/S=85/15) demonstrated greater REM sleep time reduction (p=0.0495) andNREM sleep time increase (p=0.0083), compared to racemate (R/S=50/50).These differences in REM and NREM sleep times were not observed at total100 mg/kg dose of amisulpride. There was no difference between 85/15 and50/50 in WAKE time at any doses tested in this study. The intensity ofREM sleep suppression appeared to be dose-dependent on the amount ofR-amisulpride in the total dose. Indeed, each treatment, 30 mg/kg(50/50), 30 mg/kg (85/15), 100 mg/kg (50/50), and 100 mg/kg (85/15)contained 15, 25.5, 50, and 85 mg/kg of R-amisulpride, respectively.Greater REM sleep reduction was observed in the treatment groupadministered higher doses of R-amisulpride. The effect of R-amisulprideon REM sleep suppression was saturated at higher doses (i.e. ≥50 mg/kgof R-amisulpride). Similar effects were also observed in the NREM sleeptime.

In conclusion, the fixed ratio (R/S=85/15) amisulpride exhibits greaterREM sleep time reduction and NREM sleep time increase than those ofracemate (R/S=50/50) in freely moving rats.

Examples 4-7A and 7B Human Studies

A series of human clinical studies were performed with various doses of(R)-amisulpride, (S)-amisulpride, and an 85:15 ratio by weightpercentage (w/w %) mixture of (R)-amisulpride to (S)-amisulpride.

Example 4: Dopamine D₂ Receptor Occupancy PET Study

In these human clinical studies, each of the enantiomers is administeredto healthy human subjects in single doses to determine the maximumtolerated doses.

The minimum dose of (S)-amisulpride able to occupy Dopamine D₂ receptorsin the brain at a clinically significant threshold for effect wasdetermined by administering single doses of (S)-amisulpride to healthyhuman volunteers participating in a Positron Emission Tomography (PET)clinical study. The set-point for minimum effective dose of(S)-amisulpride was the lowest dose level able to bind approximately onequarter to one third of brain Dopamine D₂ receptors in volunteers.

Dopamine D₂ occupancy of (S)-amisulpride following single oraladministration was performed in normal healthy volunteers using PositronEmission Tomography (PET) together with a highly selective D₂ PETradiotracer. Subjects were enrolled into the study with the aim ofhaving a narrow (<2-fold) prediction interval for RO₅₀ (the doserequired for 50% D2 receptor occupancy). On day −1 (prior to doseadministration), baseline PET scans (90 minutes) were performed for eachsubject and served as a control. On day 1, (S)-amisulpride was orallyadministered as a 10 ml oral solution prepared at the clinical sitepharmacy. The oral solution is a citrate buffer solution at pH 4.5containing citric acid monohydrate, trisodium citrate dihydrate andwater. The concentration can be determined from the amount of(S)-amisulpride and total volume. Dosages of 25 mg, 45 mg, 100 mg and200 mg were used. The selective D₂ PET tracer (11C PHNO) was thenadministered intravenously prior to PET scans post-dose. At apredetermined time after PET tracer administration, post-dose PET scans(90 minute) were initiated and conducted at approximately 3, 8, and 27hours post-dose. Plasma samples were collected throughout the course ofthe PET scan session and were analyzed for (S)-amisulpride levels. Theplasma concentrations peaked in a 3 hour time frame and declinedseveral-fold to near baseline levels over the 27 hour time interval. Theelimination of (S)-amisulpride was consistent with the biphasicelimination half-life reported for amisulpride, which is characterizedby an initial elimination phase of 2 to 5 hours and a terminal plasmahalf-life of approximately 12 hours. (A. J. Coukell et al, CNS Drugs6(3), 237-256 (1996))

A Simplified Reference Tissue Model (SRTM) analysis with the caudate andputamen serving as the regions of interest (ROI) and cerebellum as thereference region was employed for estimating D₂ occupancy. To moreaccurately determine the relationship between D₂ occupancy and doses ofS-amisulpride, the observed D₂ occupancy for each dose/subject wasplotted against the derived plasma concentration to determine the doselevels associated with occupancies between 30% and 50% of brain DopamineD₂ receptors.

FIG. 8 presents analytical data from the human clinical studies (n=6) onthe effects of (S)-amisulpride binding to dopamine D2 receptors. The PETscans were conducted 27 hours post-dose, and the amount of(S)-amisulpride resulting in 50% occupancy (RO₅₀) was determined to be92 mg with a ±95% confidence interval of 72 mg to 124 mg.

It was unexpectedly discovered that given the declining plasmaconcentrations, stable D2 brain occupancies were nevertheless observedout to 27 hours. In comparison, another rapidly eliminated D2antagonist, quetiapine, has an elimination half-life of about 7 hoursand a D2 occupancy trough associated with the plasma concentrationtrough. (C. L. Delaney and C. B. Nemeroff, Clin. Pharmokinetics, 40 (7),509-522 (2001); D. C. Mamo et al., J. Clin. Psychiatry, 69:1, 81-86(2008)). Thus, it was surprisingly discovered that after 27 hours (overtwo full half-lives) the brain D2 occupancy in the study (Example 6 ofthe human studies) for subjects administered an 85:15 mixture((R)-amisulpride:(S)-amisulpride) was still as high as it was at 8 hourspost dose.

Example 5: REM Suppression Study

The minimum dose of (R)-amisulpride able to significantly suppress RapidEye Movement (REM) sleep in healthy volunteers to a clinicallysignificant effect was determined by administering (R)-amisulpride, as a20 ml oral solution prepared at the clinical site pharmacy, tovolunteers participating in a polysomnography (PSG) clinical study. Theoral solution is a citrate buffer solution at pH 4.5 containing citricacid monohydrate, trisodium citrate dihydrate and water. Theconcentration can be determined from the amount of (S)-amisulpride andtotal volume. REM suppression was the biomarker used to determineclinically-significant levels of 5-HT₇ antagonism and itspharmacodynamics. REM suppression was assessed by total time in minutesspent in REM sleep and by the latency in minutes to REM sleep. It wasdetermined that an example minimum effective dose of (R)-amisulpride wasthe dose able to inhibit REM sleep by more than about 10 minutes. REMsuppression in human volunteers is an established translationalbiomarker useful to identify doses for antidepressant effects inpatients.

The dose of (R)-amisulpride able to suppress Rapid Eye Movement (REM)sleep in humans was identified in healthy subjects in a single-blind,placebo-controlled, randomized, 2-stage, 2-way crossover in-clinicpolysomnography (PSG) study of a single oral dose of (R)-amisulpride.Subjects receive a single dose of either (R)-amisulpride or placebo oneach of 2 sequential nights, subjects received drug on one night or theother of the two sequential nights. Two dose-levels of (R)-amisulpride(either 340 mg or 600 mg) were administered in the 2 different stages ofthe clinical study. The primary endpoint was REM sleep suppression asdetermined at post dose time points in the measures of latency to REMsleep, REM sleep time in minutes, and percent decrease in REM sleep timerelative to total sleep time.

FIG. 9 presents analytical data from the human clinical studies (n=33)on the effects of (R)-amisulpride in suppressing REM sleep. The REMsuppression time value is the Least Square Mean differences fromplacebo, and the error bars represent the 90% confidence interval (CI).Tables 21-23 present data from this study.

The results presented in Tables 21-23 were determined from an analysisof the date based on a linear mixed model with terms for treatment,period, and treatment sequence as fixed effects, respective baseline PSGvalue as a continuous covariate, and treatment-by-baseline PSGinteraction, and subject nested within sequence as a random effect, theKenward and Roger correction for the degrees of freedom and anunstructured covariance structure to model the intrasubject correlation.The abbreviations used in Tables 21-23 are as follows:PSG=polysomnography; CI=confidence interval; LS=least-squares; REM=rapideye movement; SE=standard error.

TABLE 21 REM Suppression and % Decrease in REM Sleep Time Primary(R)-amisulpride v Placebo PSG LS Mean Endpoint LS Mean Difference (unit)Treatment n (SE) 90% CI (SE) 90% CI REM Time Placebo 13 107.98 (98.23,117.72) −31.39 (7.99) (−45.17, −17.61) (Minutes) (5.65) (R)-amisulpride13 76.59 (5.65) (66.85, 86.33) 600 mg REM Time Placebo 20 110.05(102.08, 118.02) −18.45 (4.91) (−26.99, −9.91) (Minutes) (4.69)(R)-amisulpride 20 91.60 (4.69) (83.63, 99.57) 340 mg

TABLE 22 % Decrease in REM Sleep Time (R)-amisulpride v Placebo PrimaryPSG LS Mean Endpoint LS Mean Difference (unit) Treatment n (SE) 90% CI(SE) 90% CI REM Percent Placebo 13 24.30 (1.14) (22.33, 26.27) −6.24(1.45) (−8.87, −3.61) (%) (R)-amisulpride 13 18.06 (1.14) (16.09, 20.03)600 mg REM Percent Placebo 20 25.69 (0.92) (24.13, 27.25) −4.15 (1.09)(−6.04, −2.25) (%) (R)-amisulpride 20 21.55 (0.92) (19.98, 23.11) 340 mg

TABLE 23 Latency to REM Sleep Primary PSG (R)-amisulpride v PlaceboEndpoint LS Mean LS Mean (unit) Treatment n (SE) 90% CI Difference (SE)90% CI Latency to Placebo 13 89.06 (7.71) (75.72, 102.40) 20.30 (9.39)(3.28, 37.31) REM Sleep (Minutes) (R)-amisulpride 13 109.35 (96.01,122.69) 600 mg (7.71) Latency to Placebo 20 77.03 (9.42) (61.01, 93.04)28.23 (9.82) (11.15, 45.30) REM Sleep (Minutes) (R)-amisulpride 20105.25 (89.23, 121.27) 340 mg (9.42)

A single oral dose of 340 mg (R)-amisulpride was observed to result in adecrease in the time spent in REM sleep of 10-27 minutes, reducing theportion of the night spent in REM by 2-6 percentage points, andincreasing the latency to first REM by 11 to 45 minutes (ranges are for90% confidence intervals).

A single oral dose of 600 mg (R)-amisulpride was observed to result in adecrease in the time spent in REM sleep of 18-45 minutes, reducing theportion of the night spent in REM by 4-9 percentage points, andincreasing the latency to first REM by 3 to 37 minutes (ranges are for90% confidence intervals). Further, R-amisulpride was well tolerated inthis study. Of the 13 subjects dosed with 600 mg R-amisulpride, 3subjects reported adverse events. Vital signs and ECGs were normal.

The human clinical trials of Examples 4 and 5 identified distinctpharmacological effects between the R- and S-enantiomers of amisulpride.The dose-occupancy relationship of S-amisulpride identified minimaleffective doses of 25 mg to 100 mg for levels of D2 occupancies between20% to 50%. Additionally, a single dose of R-amisulpride (600 mg) wassufficient to produce clinically meaningful and statisticallysignificant suppression of REM sleep, indicating serotonergic (5-HT7)antagonism for R-amisulpride in humans.

Example 6: Dopamine D₂ Receptor Occupancy Study 85:15, R:S Mixture

In these human clinical studies, single oral doses of a fixed ratiocomposition of (R)-amisulpride to (S)-amisulpride of 85:15 by weightwere administered to healthy volunteers at total composition amounts of:200 mg (170 mg R-amisulpride:30 mg S-amisulpride); 300 mg (255 mgR-amisulpride:45 mg S-amisulpride); 400 mg (340 mg R-amisulpride:60 mgS-amisulpride); 600 mg (510 mg R-amisulpride:90 mg S-amisulpride); and700 mg (595 mg R-amisulpride:105 mg S-amisulpride). Doses wereadminister4ed as a 20 mL oral solution in citrate buffer.

Dopamine D2 occupancy was measured by using Positron Emission Tomography(PET) together with a highly selective D2 and PET radiotracer 11C—PHNO.PET scans were performed prior to and post dosing. Dopamine D2 receptoroccupancy was calculated for each postdose PET scan via regionalestimate of the binding potential relative to the nondisplaceablecomponent (BPND). These estimates were derived using the simplifiedreference tissue model (SRTM) with the cerebellum serving as thereference region. Brain regions of interest that were considered includethe D2-rich regions such as caudate and putamen. Identification of brainregions was performed using co-registration of PET images with eachsubject's high-resolution T1-weighted MRI (structural brain) scan.

The primary endpoint of this study was to determine the relationshipbetween the dose (total mg) of the fixed ratio composition and itsoccupancy of brain dopamine D2 receptors in healthy subjects using PET.

FIG. 10A presents data from the human clinical study (n=11) on thebinding to dopamine D₂ receptors of the 85:15 ratio by weight percentage(w/w %) composition of (R)-amisulpride to (S)-amisulpride.

The human clinical trials of Examples 4-6 determined that increasing theratio of (R)-amisulpride relative to (S)-amisulpride changes thepharmacology of the unequal enantiomeric mixtures of amisulpride.Increasing the ratio of (R)-amisulpride relative to (S)-amisulpridechanged the balance of clinically-meaningful pharmacological activitiesfrom a dopamine D₂ receptor-dominating compound (the racemate) into a5-HT₇ pharmacodynamic-preferring composition.

The human clinical trials of Examples 5 and 6 unexpectedly discoveredthat given the declining plasma concentrations, stable D2 brainoccupancies were nevertheless observed out to 27 hours. In comparison,another rapidly eliminated D2 antagonist, quetiapine, has an eliminationhalf-life of about 7 hours and a D2 occupancy trough associated with theplasma concentration trough. (C. L. Delaney and C. B. Nemeroff, Clin.Pharmokinetics, 40 (7), 509-522 (2001); D. C. Mamo et al., J. Clin.Psychiatry, 69:1, 81-86 (2008)). Thus, it was surprisingly discoveredthat after 27 hours (over two full half-lives) the brain D2 occupancy inthe study for subjects administered an 85:15 mixture((R)-amisulpride:(S)-amisulpride) was still as high as it was at 8 hourspost dose.

The human clinical trials of Examples 4 and 5 also determined that the85:15 fixed ratio composition of (R)-amisulpride to (S)-amisulprideprovided the highest ratio of overlap of 5-HT7 effect (required tosustain a decrease in the amount of REM sleep between about 20 to about45 minutes, a latency to REM sleep of about 15 minutes, and a decreasein total REM sleep time relative to total sleep time of about 5%) with aD2 occupancy in the range between about 30% to about 50%.

FIGS. 10B and 10C summarize data from Examples 4-6 and illustrates thesubstantial overlap of the 5-HT₇ effect with 30% to 50% D2 receptoroccupancy that may be achieved with administration of an 85:15 ratio byweight percentage (w/w %) mixture of (R)-amisulpride to (S)-amisulpride.FIG. 10B presents data on a racemic (50:50 ratio by weight percentagemixture of (R)-amisulpride to (S)-amisulpride) and FIG. 10C presentsdata on an 85:15 ratio by weight percentage mixture of (R)-amisulprideto (S)-amisulpride.

FIG. 10B illustrates that the desired therapeutic effect attributable toserotonin 5-HT7 antagonism cannot be achieved with a racemic mixturewithout also resulting in D2 occupancy levels associate with EPS sideeffects. For example, even for lower 5-HT7 antagonism effects (e.g.,decrease in the amount of REM sleep by about 20) the D2 occupancy isabout 78%, a level strongly associated with EPS related side effects.Accordingly, racemic amisulpride cannot provide the antidepressanteffect of (R)-(+)-amisulpride discovered by the present inventors atdosages that also have less than about 60% D2 receptor occupancy.Correspondingly, dosages of racemic amisulpride that provide less thanabout 60% D2 receptor occupancy cannot provide sufficient serotonergicantagonism to provide the discovered antidepressant effect of(R)-(+)-amisulpride.

FIG. 10C illustrates a R:S enantiomeric ratio (85:15) therapeutic agentthat provides both a desirable D2 dopamine effect at D2 occupancy levelsnot generally associated with EPS side effects and a desirableserotonergic antagonism that provides the discovered antidepressanteffect of (R)-(+)-amisulpride. In various embodiments, the presentinventors have discovered that between about 200 mg and about 700 mg oftotal amisulpride, in a R:S ratio of 85:15 by weight, can provide atherapeutic D2 dopamine effect and a therapeutic serotonergic antagonismwhilst decreasing and/or eliminating negative side effects generallyassociated with high D2 occupancy.

From another perspective, FIGS. 19A, 19B, and 19C present analyticaldata on the effects of mixtures of amisulpride.

FIG. 19A presents data from human clinical studies on the effects of(R)-amisulpride (dark circles) on 5-HT₇ (decrease in the amount of REMsleep minutes) from Example 5, where the x-axis in the top graph is50:50 racemic amisulpride, and the x-axis in the bottom graph is 85:15ratio by weight percentage (w/w %) of R:S-amisulpride. The mgdesignations indicate the amount of the indicted enantiomer in theracemic mixture (top graph) and in the 85:15 ratio of R:S amisulpride.The amount of total amisulpride is reduced by changing the mixture ofR:S amisulpride. For example, in a racemic mixture, it would require 680mg of amisulpride in order to administer 340 mg of (R)-amisulpride. Incontrast, in an 85:15 ratio of R:S, 400 mg of amisulpride would provide340 mg of (R)-amisulpride.

FIG. 19B presents data from human clinical studies on the binding todopamine D2 receptors of (S)-amisulpride and an 85:15 ratio by weightpercentage (w/w %) of (R)-amisulpride to (S)-amisulpride. The x-axis inthe top graph is 50:50 racemic amisulpride. The mg designations indicatethe amount of the indicted enantiomer in the racemic mixture (topgraph). The top graph shows the effect of (S)-amisulpride (grey circles)has on D2 occupancy based on data from Example 4. In the top graph,about 30-50% of D₂ occupancy is associated with about 77-184 mg ofracemic amisulpride, which corresponds to about 39-92 mg of(S)-amisulpride and about 39-92 mg of (R)-amisulpride. The x-axis in thebottom graph is 85:15 ratio of (R)-amisulpride to (S)-amisulpride. Themg designations indicate the amount of the indicted enantiomer in the85:15 ratio of R:S-amisulpride (bottom graph). The bottom graph showsthe effects of (S)-amisulpride (grey circles) and 85:15 ratio (whitediamonds) have on D2 occupancy based on data from Example 4 and Example6, respectively. The bottom graph shows that about 30-50% of D2occupancy is associated with about 257-614 mg of 85:15 ratio ofR:S-amisulpride, which corresponds to about 39-92 mg of (S)-amisulprideand about 218-522 mg of (R)-amisulpride. As readily apparent, the ratioof 85:15 R:S amisulpride provides a greater amount of R enantiomer thanS enantiomer.

FIG. 19C illustrates the substantial overlap of the 5-HT₇ effect with30% to 50% D2 receptor occupancy that can be achieved withadministration of an 85:15 ratio of (R)-amisulpride to (S)-amisulpride.The x-axis in the top graph is the total amount of racemic amisulpride.The mg designations indicate the amount of the indicted enantiomer inthe racemic mixture. The grey shaded circles are the data for(S)-amisulpride from Example 4, showing the effect of (S)-amisulpridehas on D2 occupancy. The dark circles are the data for (R)-amisulpridefrom Example 5, showing the effect of (R)-amisulpride has on 5-HT₇. Thex-axis in the bottom graph is the total amount of 85:15 ratio R:Samisulpride. The mg designations indicate the amount of the indictedenantiomer in the 85:15 ratio mixture (bottom graph). The grey shadedcircles are the data for (S)-amisulpride from Example 4, showing theeffect of (S)-amisulpride has on D2 occupancy. The dark circles are thedata for (R)-amisulpride from Example 5, showing the effect of(R)-amisulpride has on 5-HT₇. The white diamonds are data for the 85:15ratio R:S amisulpride from Example 6 (D2 occupancy).

As can be seen in FIG. 19C top graph, about 30-50% of D₂ occupancy isassociated with about 77-184 mg of racemic amisulpride, whichcorresponds to about 39-92 mg of (S)-amisulpride and about 39-92 mg of(R)-amisulpride (top graph). However, about 39-92 mg of (R)-amisulprideis not enough to achieve sufficient 5-HT₇ effect associated with thediscovered antidepressant activity. As shown on the dotted line andsolid black circles, 340 mg of (R)-amisulpride provides a decrease inREM sleep by about 20 minutes. 340 mg of (R)-amisulpride projected ontothe curve of racemic amisulpride (solid line) shows that the D₂occupancy is 78%, which is in the range that is associated with sideeffects. Similarly, as shown on the dotted line and solid black circles,600 mg of (R)-amisulpride provides a decrease in REM sleep by about 30minutes. 600 mg of (R)-amisulpride projected onto the curve of racemicamisulpride (solid line) shows that the D2 occupancy is 86%, which abovethe occupancy level associated with significant dopamine D2 receptoroccupancy side effects.

Also, as shown in FIG. 19C bottom graph, about 275-614 mg of amisulpride(85:15 ratio of R:S) provides about 30-50% D₂ antagonism. The amount ofabout 257-614 mg (85:15 ratio of R:S) corresponds to about 39-92 mg(S)-amisulpride and about 218-522 mg (R)-amisulpride. The ratio of 85:15R:S amisulpride provides a greater amount of R enantiomer than the Senantiomer. This in turn allows for administration of greater amount of(R)-amisulpride than (S)-amisulpride in order to avoid side effectsassociated with D₂ occupancy while, as the inventors have discovered,still providing sufficient 5-HT7 effect. A racemic mixture ofamisulpride does not and cannot provide this unequal amount of (R) and(S)-amisulpride. The inventors have thus discovered that the ratio of85:15 R:S amisulpride provides a substantial overlap in the doseintervals of the two enantiomers that achieves their respective D2 and5-HT7 effects.

Example 7A: Human Clinical Studies (PK and QT Interval)

In Part 1 of these human clinical studies, single solid oral doses of afixed ratio composition of (R)-amisulpride to (S)-amisulpride of 85:15by weight were administered to healthy volunteers at total compositionamounts of 200 mg (170 mg R-amisulpride:30 mg S-amisulpride). Threeformulations were studied, an IR formulation and three MR matrix tabletformulations, as set forth in Table 24A. Each human volunteer was dosedwith various formulations with a 7-day wash out period betweenformulation switch. The effects of each formulation on a subject weremonitored for 48 hours.

In Part 2 of these human clinical studies, single solid oral doses of afixed ratio composition of (R)-amisulpride to (S)-amisulpride of 85:15by weight were administered to healthy volunteers at total compositionamounts of 200 mg (170 mg R-amisulpride:30 mg S-amisulpride). Fourformulations were studied, an IR formulation and two MR matrix tabletformulations, as set forth in Table 24B, and the formulation of Lot 3Zset forth in Table 24A. Each human volunteer was dosed with variousformulations with a 7-day wash out period between formulation switch.The effects of each formulation on a subject were monitored for 48hours.

In both Part 1 and Part 2, blood plasma concentrations of totalamisulpride (R and S enantiomers combined) were measured 3 hourspre-dose (±15 minutes), within 15 minutes of dosing, at the followingtime intervals post-dose (±5 minutes): 10, 20, 30, 45 60, 80, 100, 120,140, 160, 180, 200, 220, 240, 260, 280 minutes; 24 hours post-dose (±15minutes); 27 hours post-dose (±15 minutes), and 48 hours post-dose (±15minutes).

TABLE 24A Compositions MR Tablets Example 7A Lot 2Z Lot 3Z Lot 4Z (10%)(25%) (15%) Component Function mg/tab mg/tab mg/tab Intra-(R)-amisulpride API 170 170 170 granular (S)-amisulpride API 30 30 30component D-Mannitol*¹ Filler 29.5 29.5 29.5 Pregelatinized starchFiller 29.5 29.5 29.5 Polyvinyl alcohol Binder 5.5 5.5 5.5 Purifiedwater*² (binder solvent) Solvent 72 72 72 Subtotal (granule component)*⁵264.5 264.5 264.5 Extra- Hypromellose*³ Extended 50.0 125.0 75.0granular release agent component D-Mannitol*⁴ Filler 178.0 103.0 153.0Magnesium stearate Lubricant 7.5 7.5 7.5 Total tablet weight (mg) 500500 500 *¹Crystalline powder, Pearlitol 50C (Roquette) *²Water isremoved during processing. *³Metolose SR 90SH-100SR (Shin Etsu) *⁴Spraydried powder, Pearlitol 100SD (Roquette) *⁵After water removed duringprocessing

TABLE 24B Compositions MR Tablets Example 7A Part 2 only Lot 5Z Lot 6Z(20%) (40%) Component Function mg/tab mg/tab Intra-granular(R)-amisulpride API 170 170 component (S)-amisulpride API 30 30D-Mannitol*¹ Filler 29.5 29.5 Pregelatinized starch Filler 29.5 29.5Polyvinyl alcohol Binder 5.5 5.5 Purified water*² Solvent 72 72 (bindersolvent) Subtotal (granule component)*⁵ 264.5 264.5 Extra-Hypromellose*³ Extended 100.0 200.0 granular release agent componentD-Mannitol*⁴ Filler 128.0 28.0 Magnesium stearate Lubricant 7.5 7.5Total tablet weight 500 500 *¹Crystalline powder, Pearlitol 50C(Roquette) *²Water is removed during processing. *³Metolose SR90SH-100SR (Shin Etsu) *⁴Spray dried powder, Pearlitol 100SD (Roquette)*⁵Water is removed during processing

TABLE 25 Composition IR Tablet (Lot 1Z) Example 7A Part 1 and Part 2Quantity Component Function (mg/tablet) Core Tablet (R)-amisulpride API170.0 (S)-amisulpride API 30.0 D-Mannitol Filler 167.5 Partlypregelatinized starch Filler 100.0 Partially hydrolyzed polyvinyl Binder10.0 alcohol Purified water*² Granulation Solvent q.s. Croscarmellosesodium Disintegrant 15.0 Magnesium stearate Lubricant 7.5 Weight of Coretablet 500.0 Film Coat Suspension Hypromellose Coating agent 3.78Macrogol 400 Coating agent 0.38 Titanium oxide Coating agent 1.89 TalcCoating agent 1.36 Yellow ferric oxide Coloring agent 0.11 Red ferricoxide Coloring agent 0.05 Purified water Coating solvent q.s. Carnaubawax Polishing agent 0.01 Total Weight 507.58 q.s. means quantumsufficiat (as much as necessary)

FIGS. 22A-22D present data on the average blood plasma concentrations oftotal amisulpride (R and S enantiomers combined) as a function of timefor twelve subjects (n=12) in Part 1 of this study. TABLE 26A lists thedata plotted in FIGS. 22A-22D and also provides the standard deviation(σ) of the average. FIGS. 22A-22D present data for subjects who weresuccessfully administered all of the formulations of Part 1 of Example7A (n=12) that is for subjects who each administered Lot 1Z, Lot 2Z, Lot4Z, Lot 3Z, and Lot 3Z fed state.

FIGS. 22E-22K present data on the average blood plasma concentrations oftotal amisulpride (R and S enantiomers combined) as a function of timefor subjects in Part 1 and Part 2 of this example. The data presentedfor the subjects of Part 1 differs from that presented in FIGS. 22A-22Din that data for all subjects is presented in FIGS. 22E, 22F, 22H and22I. FIGS. 22Gm 22J and 22K present data on subjects in Part 2 of thisstudy. Eighteen subjects were administered Lot 5Z (n=18 for most timepoints), and seventeen subjects were administered Lot 6Z (n=17 for mosttime points) in Part 2 of this study. Tables 26B and 26C list the dataplotted in FIGS. 22E-22K and also provides the standard deviation (σ) ofthe average.

TABLE 26A Average Blood Plasma Concentration of Amisulpride (ng/mL) andStandard Deviation (σ) (n = 12) of data plotted in FIGS. 22A-22D Lot 3Z(25%) Time Lot 1Z (IR) Lot 2Z (10%) Lot 4Z (15%) Lot 3Z (25%) Fed State(hours) [ng/mL] σ [ng/mL] σ [ng/mL] σ [ng/mL] σ [ng/mL] σ 0 0.53 0.100.53 0.10 0.50 0.00 0.50 0.00 0.50 0.00 0.17 7.64 9.86 1.03 0.92 1.351.49 0.83 0.70 0.50 0.00 0.33 46.82 40.56 12.28 26.25 6.23 5.01 4.626.08 0.63 0.33 0.5 80.46 55.85 24.60 38.51 13.40 11.45 10.10 9.18 1.321.46 0.75 132.02 72.99 56.75 38.66 32.19 19.96 16.73 11.38 4.13 4.59 1134.57 67.22 72.33 38.40 40.79 22.74 20.97 9.27 9.77 10.65 1.33 156.44121.71 81.96 44.44 46.82 30.52 35.74 13.64 28.19 40.00 1.67 182.95162.32 102.82 62.52 58.02 37.32 45.98 23.33 49.30 73.57 2 257.93 254.93143.33 125.72 66.08 41.41 73.88 58.22 61.97 70.94 2.33 370.72 391.80176.38 180.37 88.71 60.61 98.21 85.95 91.63 103.76 2.67 356.56 318.41224.82 259.16 147.55 158.90 116.45 98.53 113.34 124.23 3 337.22 252.92272.19 346.48 185.52 176.82 124.83 93.35 124.95 101.15 3.33 320.33185.11 271.03 288.35 218.63 219.97 124.75 73.57 141.30 129.53 3.67345.92 177.01 288.08 247.01 243.91 206.05 134.04 66.44 146.42 128.12 4345.92 148.68 305.14 234.27 244.77 172.26 156.81 86.32 157.43 106.424.33 376.75 180.40 343.17 214.91 234.06 111.57 169.28 92.11 174.15116.29 4.67 357.75 179.05 368.17 170.25 224.25 90.07 197.43 86.48 214.65112.30 5 343.92 132.76 345.58 149.74 235.25 87.69 184.88 96.64 230.7699.92 5.5 288.08 87.67 303.58 137.95 237.79 133.68 169.12 79.79 238.7583.73 6 267.50 86.62 286.50 149.56 219.28 127.58 154.79 67.05 230.5070.59 6.5 223.67 67.02 245.50 115.15 210.17 119.65 144.68 64.10 205.2056.65 7 209.33 69.27 221.63 93.77 181.59 80.57 136.45 57.70 188.71 53.947.5 195.58 66.44 198.83 77.97 173.44 73.53 126.19 52.11 163.64 50.69 8189.25 81.10 182.48 72.36 156.98 64.91 118.13 46.18 145.83 46.48 9154.33 57.16 156.95 64.70 135.54 63.07 105.87 43.95 119.80 38.25 10130.31 45.56 133.57 58.64 116.03 53.70 92.68 36.34 101.15 32.23 11111.89 49.19 113.67 50.63 93.29 39.68 81.10 33.98 84.08 27.58 12 92.9933.61 99.89 42.28 82.59 33.74 70.23 26.78 69.77 20.65 14 77.87 26.0977.50 29.25 64.01 23.95 59.75 21.41 56.53 16.30 16 61.58 19.88 64.9926.08 54.32 19.12 48.86 16.62 47.40 14.09 18 51.79 17.94 54.04 21.6545.04 15.39 42.49 15.15 38.95 12.08 20 43.29 16.05 47.29 19.19 40.8913.89 38.72 13.60 33.93 10.15 22 36.06 11.99 39.46 16.22 35.37 11.3335.62 13.45 30.58 9.08 24 31.17 9.84 34.82 13.23 31.39 9.82 32.02 12.6028.62 8.57 27 26.68 8.44 30.03 11.23 25.08 8.20 28.67 12.45 23.72 7.4248 8.76 5.07 10.93 5.61 10.62 5.38 11.54 7.24 10.17 5.84

TABLE 26B Average Blood Plasma Concentration of Amisulpride (ng/mL) andStandard Deviation (σ) of data plotted in FIGS. 22E, 22F, 22H, and 22ILot 3Z (25%) Time Lot 1Z (IR) Lot 2Z (10%) Lot 4Z (15%) Lot 3Z (25%) FedState (hours) [ng/mL] σ [ng/mL] σ [ng/mL] σ [ng/mL] σ [ng/mL] σ 0 0.84NC 0.85 NC NC NC NC NC NC NC 0.17 9.01 9.63 2.33 3.1 1.95 1.75 1.41 0.96NC NC 0.33 39.8 37.7 12.5 24 6.26 4.98 3.95 5.56 1.29 0.389 0.5 68.654.5 24.7 35.3 11.8 11.3 8.39 8.48 1.6 1.61 0.75 118 75.8 63.5 46.5 29.619.8 17.5 12.8 4.13 4.59 1 131 61.8 82.1 48.2 40.2 23.6 26.4 21.5 9.7710.6 1.33 170 114 92.8 46.4 51.4 35.6 41.9 27.6 28.2 40 1.67 186 143 11967.6 64.7 39.9 55.8 39.4 49.3 73.6 2 241 219 166 127 75.4 45.4 80.8 58.462 70.9 2.33 319 338 193 165 97.9 60.7 119 97.8 91.6 104 2.67 316 279249 240 149 146 146 124 113 124 3 323 241 300 324 181 163 179 205 125101 3.33 338 231 331 329 213 203 188 215 141 130 3.67 368 215 343 277239 190 196 203 146 128 4 372 187 342 234 262 176 193 150 157 106 4.33419 249 378 224 290 227 201 130 174 116 4.67 391 207 377 161 274 196 215109 215 112 5 392 199 357 147 259 116 201 111 231 99.9 5.5 308 111 308131 246 126 183 92.5 239 83.7 6 281 97.1 285 137 227 120 168 81.2 23170.6 6.5 235 72 247 113 215 111 157 73.2 205 56.6 7 222 73.3 225 92.3188 76.5 149 66.5 189 53.9 7.5 200 67.6 202 74.7 177 68.4 137 60.5 16450.7 8 190 78.2 188 72.6 161 60.6 130 57.6 146 46.5 9 154 55.5 159 62.8137 58.2 114 49.4 120 38.3 10 131 44.8 135 56.4 119 49.8 94.6 36.1 10132.2 11 114 46.1 114 48.6 94.5 36.6 84.9 35.6 84.1 27.6 12 93 32.7 10041.9 82.6 31.1 73.5 28.7 69.8 20.6 14 76.5 25.9 78.8 30.7 64.2 22 61.121.6 56.5 16.3 16 60.4 19.7 65.6 26.3 53.9 17.7 50.8 18.3 47.4 14.1 1849.5 17.5 54.5 22.1 44.5 14.2 43.3 15.3 39 12.1 20 41.3 15.6 47.7 18.840.5 12.9 39.2 13.7 33.9 10.2 22 35.7 12.2 39.5 15.8 34.9 10.6 35.4 13.130.6 9.08 24 31.3 10.1 34.8 13.1 30.8 9.23 32.5 12.5 28.6 8.57 27 25.78.28 29.9 11.8 24.7 7.8 28.9 12.6 23.7 7.42 48 9.12 4.98 10.7 5.2 10.65.05 11.6 6.89 10.2 5.84 NC = not calculated

TABLE 26C Average Blood Plasma Concentration of Amisulpride (ng/mL) andStandard Deviation (σ) of data plotted in FIGS. 22G, 22J and 22K Lot 1Z(IR) Lot 3Z (25%) Lot 5Z (20%) Lot 6Z (40%) Time Part 2 Part 2 Part 2Part 2 (hours) [ng/mL] σ [ng/mL] σ [ng/mL] σ [ng/mL] σ 0 NC NC NC NC NCNC NC NC 0.17 7.01 14 2.18 2.88 0.87 0.53 1.18 0.52 0.33 53.3 57.1 5.757.06 3.97 3.44 5.42 4.81 0.5 107 123 12.4 12.7 7.86 5.72 10.2 6.85 0.75128 98.9 26.3 16.5 17 14 20 12.8 1 136 84.9 38.2 23.8 32.5 23.2 25.216.4 1.33 149 74.6 42.4 27.1 51.4 32.4 33.4 19.7 1.67 172 82.1 53 29.162.9 44.4 38.6 22.5 2 238 176 65.3 29.7 82 50.9 53.2 37 2.33 297 23674.7 25.5 102 64.3 81.8 79.4 2.67 362 340 87.7 30.7 114 75.5 99.5 87.2 3401 330 101 54.5 136 93.8 132 134 3.33 449 276 142 111 164 115 166 1693.67 501 280 180 135 180 108 170 157 4 525 294 221 150 203 109 185 1644.33 522 261 257 143 276 181 208 136 4.67 478 228 280 153 325 216 251170 5 452 199 357 209 330 189 244 178 5.5 403 203 343 228 336 228 234130 6 354 163 292 200 287 183 204 111 6.5 294 123 239 130 230 127 173 877 271 109 215 111 205 109 157 72.7 7.5 237 84.3 183 96 183 90 139 63.7 8217 83.8 168 85.9 173 78.9 130 53.3 9 180 66.8 137 62.7 150 63.4 10641.9 10 153 55.3 121 53.4 129 55 94.2 41.5 11 122 46.1 104 42.1 108 42.683.5 33.5 12 107 39.5 88.4 37 97.3 41.7 77.2 34.8 14 78 22.7 66.9 28.873.1 31.4 64 28.3 16 64.2 25.7 56 24.5 62.3 27.9 56.1 23.1 18 53.1 14.247.3 19.2 50.7 20.7 46.6 20.2 20 46.1 18.1 41 15.8 44.6 18.7 42.1 19.522 39.9 15.4 36.8 14.4 38.4 15.4 38.7 18.7 24 35.9 15.2 33 13.3 34.914.3 36.8 19.4 27 29.9 12.1 28.3 11.7 29.8 12.2 35 17.4 48 9.91 5.0110.7 4.93 12.2 7.38 12.9 7.11 NC = not calculated

FIGS. 20A-20B present, respectively, the geometric mean of Cmax and AUCfor the subjects of Part 1 of this study. The error bars in FIGS.20A-20B represent the 95% confidence intervals. FIGS. 20A-20B presentdata for subjects who were successfully administered all of theformulations of Part 1 of Example 7A (n=12) that is for subjects whoeach administered Lot 1Z, Lot 2Z, Lot 4Z, Lot 3Z, and Lot 3Z fed state.Table 27A presents the data plotted in FIGS. 20A-20B. The data in Table27A presents the geometric mean of the subjects' Cmax and AUC, the lower95% confidence interval (L CI) and upper 95% confidence interval (U CI).

FIGS. 20C-20D present, respectively, the geometric mean of Cmax and AUCfor the subjects of Part 2 of this study (filled squares) compared tothe subjects of Part 1 (open squares). The error bars in FIGS. 20C-20Drepresent the 95% confidence intervals.

Tables 27B and 27C present the data plotted in FIGS. 20C-20D. The datain Tables 27B and 27C presents the geometric mean of the subjects' Cmaxand AUC, the lower 95% confidence interval (L CI), upper 95% confidenceinterval (U CI), and coefficient of variation (CV %). Table 27B presentsdata for subjects of Part 1 of this study for all subjects administeredthe respective formulation. Table 27C presents data for subjects of Part2 of this study for all subjects administered the respectiveformulation.

FIGS. 21A-21B present, respectively, average Cmax and AUC for thesubjects of Part 1 of this study where the values for Cmax and AUC havebeen normalized for each subject to the Cmax and AUC value of thatsubject when administered the IR tablet, i.e. a tablet having acomposition substantially similar to that of Lot 1Z. FIG. 21C presentsaverage Tmax data for the subjects of Part 1 of this study. The errorbars in FIGS. 21A-21C represent the 95% confidence intervals. FIGS.21A-21C present data for subjects who were successfully administered allof the formulations of Part 1 of Example 7A (n=12) that is for subjectswho each administered Lot 1Z, Lot 2Z, Lot 4Z, Lot 3Z, and Lot 3Z fedstate.

FIGS. 21D-21E present, respectively, geometric mean Cmax and AUC for thesubjects of Part 2 of this study (filled squares) compared to thesubjects of Part 1 (open squares) where the values for Cmax and AUC havebeen normalized for each subject to the Cmax and AUC value of thatsubject when administered the IR tablet, i.e. a tablet having acomposition substantially similar to that of Lot 1Z. FIG. 21F presentsgeometric mean Tmax data for the subjects of Part 2 of this study(filled squares) compared to the subjects of Part 1 (open squares). Theerror bars in FIGS. 21D-21F represent the 95% confidence intervals.

Table 28A presents the data plotted in FIGS. 21A-21B, Table 29A presentsCmax and AUC data on individual subjects in Part 1 of this study, andTable 30A presents Tmax data on individual subjects in Part 1 of thisstudy. The data in Table 28A presents the normalized average of thesubjects' Cmax and AUC where an individual subject's Cmax and AUC wasnormalized to their IR value, the standard deviation, and the lower 95%confidence interval (L CI) and upper 95% confidence interval (U CI).

Tables 28B and 28C present the data plotted in FIGS. 21D-21E, Table 29Bpresents Cmax and AUC data on individual subjects in Part 2 of thisstudy, and Table 30B presents Tmax data on individual subjects in Part 2of this study.

The data in Table 28B presents the normalized average of the subjects'Cmax and AUC for all subjects administered the respective formulation inPart 1 of this study where an individual subject's Cmax and AUC wasnormalized to their IR value, the lower 95% confidence interval (L CI)and upper 95% confidence interval (U CI).

The data in Table 28C presents the normalized average of the subjects'Cmax and AUC for all subjects administered the respective formulation inPart 2 of this study where an individual subject's Cmax and AUC wasnormalized to their IR value, the lower 95% confidence interval (L CI)and upper 95% confidence interval (U CI).

Table 31A presents data on the ratio of the total amisulpride AUC fromadministration to Tmax (AUC_(0-Tmax)) to total amisulpride AUC fromadministration to infinity (AUC_(0-INF)), on individual subjects in Part1 of this study and the average ratio (±the 95% confidence interval forthe average) for various compositions. The AUC is given in units ofhr*ng/mL.

Table 31B presents data on the ratio of the total amisulpride AUC fromadministration to Tmax (AUC_(0-Tmax)) to total amisulpride AUC fromadministration to 48 hours (AUC₀₋₄₈) on individual subjects in Part 1 ofthis study and the average ratio (±the 95% confidence interval for theaverage) for various compositions. The AUC is given in units ofhr*ng/mL.

Table 31C presents data on the ratio of the total amisulpride AUC fromadministration to Tmax (AUC_(0-Tmax)) to total amisulpride AUC fromadministration to 48 hours (AUC₀₋₄₈) on individual subjects in Part 2 ofthis study and the average ratio (±the 95% confidence interval for theaverage) for various compositions. The AUC is given in units ofhr*ng/mL.

In Parts 1 and 2 of this study, the pharmacokinetics of an immediaterelease formulation (Lot 1Z) was compared with that of various modifiedrelease formulations in subjects following oral administration. The Cmaxobserved in Part 1 following administration of the modified releaseformulation of Lot 3Z (geometric mean=238 ng/mL) is reduced relative tothe Cmax value observed for the immediate release formulation (geometricmean=567 ng/mL). In this study, the Cmax observed followingadministration of the modified release formulation of Lot 3Z isapproximately 50% of the Cmax observed following administration of theimmediate release formulation of Lot 1Z. The reduction in Cmax observedwith the modified release formulation Lot 3Z is accompanied by adecrease in bioavailability. AUC decreased to approximately 60% of thatof the IR formulation. When administered in a fed state, the modifiedrelease formulation of Lot 3Z maintained similar Cmax and AUC values,but had a longer Tmax compared to the immediate release formulation ofLot 1Z.

It was observed in Part 2 that following administration of the modifiedrelease formulation of Lot 5Z the maximum concentration of totalamisulpride was reached at between 2.33 and 7 hours post dose (median4.84 h), after which concentrations followed a biphasic or triphasicdecline, remaining quantifiable up to the final sampling time point of48 hours post-dose in all subjects. Elimination of the modified releaseformulation of Lot 5Z had a geometric mean half-life of 15-15.5 hours.The modified release formulation of Lot 5Z resulted in an approximate33-37% reduction in Cmax and an approximate 24-28% reduction inAUC(0-48), compared to an immediate release formulation (Lot 1Z) at thesame dose level. Elimination half-life was relatively unchanged withrespect to the immediate release (IR) formulation, a small increase ofapproximately 2.5 hours was observed. Variability of all parameters wassimilar between the IR formulation and the modified release formulationof Lot 5Z.

It was observed that following administration of the modified releaseformulation of Lot 6Z maximum concentration of total amisulpride wadreached at between 2.33 and 6 hours post dose (median 4.67 h), afterwhich concentrations followed a biphasic or triphasic decline, remainingquantifiable up to the final sampling time point of 48 hours post-dosein all subjects. Elimination of the modified release formulation of Lot6Z had a geometric mean half-life of 15.9-16.1 hours. The modifiedrelease formulation of Lot 6Z resulted in an approximate 51-54%reduction in Cmax and an approximate 38-42% reduction in AUC(0-48),compared an immediate release formulation (Lot 1Z) at the same doselevel. Elimination half-life was relatively unchanged with respect tothe immediate release (IR) formulation with a small increase ofapproximately 3.5 hours. Variability of AUC parameters was similarbetween the IR tablet and the modified release formulation of Lot 6Z,however variability was slightly increased for Cmax.

In this study the “fed state” was achieved by providing a breakfastconsumed over a maximum period of 25 min, with dosing occurring 30 minafter the start of breakfast. Subjects were encouraged to eat their mealevenly over the 25 min period, and must have completed 90% of meal inorder to be dosed.

TABLE 27A Cmax (ng/mL) and AUC (ng*h/mL) for Various Compositions inPart 1 Lot3Z Lot 1Z Lot 2Z Lot 4Z Lot 3Z (25%) Parameter IR (10%) (15%)(25%) Fed State Cmax  567  424  297  238  269 L CI  411  275  206  176 210 U CI  780  652  429  210  345 AUC 3811 3426 2715 2478 2615 L CI3157 2594 2033 1831 2027 U CI 4600 4525 3627 3353 3374

TABLE 27B Cmax (ng/mL) and AUC (ng*h/mL) for Various Compositions inPart 1 (all subjects) Lot 1Z Lot 2Z Lot 4Z Lot 3Z Lot 3Z (25%) ParameterIR (10%) (15%) (25%) Fed State Cmax 567 462 337 252 269 L CI 437 331 238186 210 U CI 736 645 477 342 345 CV % 54.1 66.0 65.9 62.0 38.0 AUC 36003360 2660 2330 2350 L CI 3040 2720 2120 1830 1870 U CI 4270 4150 33402960 2950 CV % 33.9 39.7 41.1 47.7 34.8

TABLE 27C Cmax (ng/mL) and AUC (ng*h/mL) for Various Compositions inPart 2 Lot 1Z Lot 5Z Lot 3Z Lot 6Z Parameter IR (20%) (25%) (40%) Cmax634 390 397 298 L CI 477 289 297 213 U CI 842 527 531 417 CV % 57.3 66.556.4 72.8 AUC ₍₀₋₄₈₎ 4120 2910 2790 2510 L CI 3420 2390 2270 2060 U CI4970 3540 3430 3060 CV % 36.3 41.2 38.4 39.9

TABLE 28A Normalized Cmax and AUC for Various Compositions in Part 1(subjects who were successfully administered all of the formulations ofPart 1 of Example 7A (n = 12)) Lot 1Z Lot 2Z Lot 4Z Lot 3Z Lot 3Z (25%)Parameter IR (10%) (15%) (25%) Fed State Cmax 1 0.781 0.595 0.453 0.556SD n/a 0.230 0.363 0.169 0.375 L CI n/a 0.626 0.351 0.339 0.304 U CI n/a0.936 0.839 0.566 0.808 AUC 1 0.893 0.713 0.631 0.686 SD n/a 0.148 0.2340.186 0.268 L CI n/a 0.794 0.556 0.506 0.506 U CI n/a 0.992 0.870 0.7560.866

TABLE 28B Normalized Cmax and AUC for Various Compositions in Part 1(all subjects) Lot 1Z Lot 2Z Lot 4Z Lot 3Z Lot 3Z (25%) Parameter IR(10%) (15%) (25%) Fed State Cmax 1 0.791 0.596 0.461 0.487 L CI n/a0.622 0.431 0.358 0.345 U CI n/a 1.01 0.824 0.593 0.688 AUC 1 0.8990.733 0.654 0.658 L CI n/a 0.805 0.610 0.567 0.533 U CI n/a 1.00 0.8820.754 0.811

TABLE 28C Normalized Cmax and AUC for Various Compositions in Part 2 Lot1Z Lot 5Z Lot 3Z Lot 6Z Parameter IR (20%) (25%) (40%) Cmax 1 0.6450.637 0.483 L CI n/a 0.493 0.508 0.392 U CI n/a 0.845 0.798 0.595 AUC 10.735 0.683 0.603 L CI n/a 0.644 0.603 0.521 U CI n/a 0.838 0.773 0.699

TABLE 29A Cmax and AUC by Subject for Various Compositions in Part 1 Lot3Z (25%) Lot 2Z (10%) Lot 4Z (15%) Lot 3Z (25%) Fed State Lot 1Z IRSubject Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC  1  230 2015 1251388 85.8  982 134 1364  424 2699  2  417 3050 262 2930 270 2820 NC NC 494 3580  5  406 3300 992 3600 330 3390 NC NC 1110 4760  6 1080 5470 NCNC 936 5190 NC NC  933 5660  7 1260 5568 634 3583 305 2613 252 2821 12005280  8 NC NC NC NC NC NC NC NC  813 4390 12  652 4162 589 4005 246 2640206 2293  325 2933 13  212 2366 232 1990 158 1615 243 2169  402 2907 16 525 3735 778 4306 242 2792 311 2975  497 3348 17  165 2292 188 3362 1643841 379 4076  240 3182 18  590 4564 375 3214 366 3267 304 2050  6584494 20  538 3112 301 3128 342 2923 529 4137 1070 4291 21 NC NC NC NC 931090 NC NC  248 1740 22  789 5358 334 3299 241 3096 191 2466  861 503123  229 1908 161 1125 270 1334 199 1421  458 2435 25  392 5390 325 3750257 3439 309 2654  429 4796 26  664 4296 300 2952 408 3579 296 3396  6654925 NC = not calculated

TABLE 29B Cmax and AUC by Subject for Various Compositions in Part 2 Lot5Z (20%) Lot 3Z (25%) Lot 6Z (40%) Lot 1Z (IR) Subject Cmax AUC Cmax AUCCmax AUC Cmax AUC  78  454 2210 459 1920 356 1520 1070 3920  79  5623910 257 2440 121 1660  386 3470  80  870 5450 442 3690 560 3690 12207640  81  595 3450 603 4000 514 3110 1470 5800  83  194 2360 575 2520367 2320  609 2770  84  512 2980 736 3370 513 3230  912 5470  85  2022240 364 2830 268 2260  564 3780  91  618 3320 453 2320 454 2130  9584610  93  353 1460 118 1140 98.2 1090  245 1990  97  425 4130 634 3600244 2690  570 5510  99  740 5150 923 5720 281 3490  781 6150 102  1372410 261 2240 84.1 1820  300 2840 107  347 2090 331 3420 611 5370  7984610 111  249 1390 NC NC NC NC NC NC 112  133 2250 303 2840 295 2380 294 2920 113 1040 4640 NC NC 856 3540  807 4580 114  283 3220 NC NC 1962950 NC NC 115  514 3570 244 2480 238 2420  494 3660 NC = not calculated

TABLE 30A Tmax (hours) by Subject for Various Compositions in Part 1 Lot2Z Lot 4Z Lot 3Z Lot 3Z (25%) Lot 1Z (10%) (15%) (25%) Fed State IR TmaxTmax Tmax Tmax Tmax Subject (hours) (hours) (hours) (hours) (hours) 13.33 4.67 3.33 6 2.67 2 3.67 5.00 4.33 NC 3.67 5 4.33 4.33 3.67 NC 4.336 3.33 NC 3.33 NC 3.33 7 3 3 2.67 5.5 2.33 8 NC NC NC NC 5.00 13 2 3.674 5.5 2.33 16 4.33 3.67 4.67 4.33 4 17 4.67 6.5 4 5.5 5 18 4.67 3.67 55.5 3.67 20 5 5 2.33 3.67 2.33 21 NC NC 5.0 NC 4.40 22 4.33 4.67 4.67 74.67 23 4.33 4.33 4.33 5.5 4.33 25 5.5 5.5 5.5 5 6 26 2.33 3 4.33 6.51.67 NC = not calculated

TABLE 30B Tmax (hours) by Subject for Various Compositions in Part 2 Lot5Z (20%) Lot 3Z (25%) Lot 6Z (40%) Lot 1Z (IR) Subject Tmax (hours) Tmax(hours) Tmax (hours) Tmax (hours) 78 3.33 3.33 2.33 3.67 79 5.50 4.005.00 4.33 80 5.50 4.33 4.00 4.00 81 4.33 5.00 3.00 3.00 83 2.33 4.003.33 2.67 84 4.67 5.00 5.50 5.50 85 5.00 4.67 4.67 4.67 91 4.33 4.004.67 2.33 93 4.67 4.00 5.00 5.00 97 5.00 5.50 5.50 4.67 99 5.50 5.506.00 4.00 102 6.00 5.50 6.00 4.33 107 5.00 5.50 4.00 3.67 111 4.67 NC NCNC 112 7.00 5.00 4.67 4.00 113 4.67 NC 5.00 4.33 114 4.00 NC 4.33 NC 1156.00 13.67 4.67 3.33 NC = not calculated

TABLE 31A (AUC_(0-Tmax))/(AUC_(0-INF)), for Various Compositions in Part1 Lot 1Z Lot 2Z Lot 4Z Lot 3Z Lot 3Z (25%) (IR) (10%) (15%) (25%) FedState AUC_(0-Tmax) AUC_(0-Tmax) AUC_(0-Tmax) AUC_(0-Tmax) AUC_(0-Tmax)Subject AUC_(0-INF) AUC_(0-INF) AUC_(0-INF) AUC_(0-INF) AUC_(0-INF) 10.137 0.135 0.245 0.131 0.331 7 0.141 0.132 0.123 0.063 0.163 12 0.3240.279 0.181 0.133 0.176 13 0.136 0.064 0.185 0.152 0.187 16 0.185 0.1280.141 0.117 0.151 17 0.179 0.154 0.178 0.074 0.154 18 0.227 0.276 0.1510.162 0.214 20 0.121 0.145 0.122 0.055 0.220 22 0.161 0.151 0.145 0.1080.210 23 0.318 0.189 0.179 0.142 0.313 25 0.240 0.181 0.125 0.123 0.15926 0.082 0.103 0.136 0.175 0.282 Average 0.19 ± 0.04 0.16 ± 0.04 0.16 ±0.02 0.12 ± 0.02 0.21 ± 0.04

TABLE 31B (AUC_(0-Tmax))/(AUC₀₋₄₈), for Various Compositions in Part 1Lot 1Z Lot 2Z Lot 4Z Lot 3Z Lot 3Z (25%) (IR) (10%) (15%) (25%) FedState AUC_(0-Tmax) AUC_(0-Tmax) AUC_(0-Tmax) AUC_(0-Tmax) AUC_(0-Tmax)Subject AUC₀₋₄₈ AUC₀₋₄₈ AUC₀₋₄₈ AUC₀₋₄₈ AUC₀₋₄₈ 1 0.138 0.141 0.2650.132 0.337 2 0.254 0.213 0.224 0.186 NC 5 0.243 0.315 0.216 0.154 NC 60.164 0.157 NC 0.168 NC 7 0.144 0.136 0.128 0.066 0.173 8 0.191 NC NC NCNC 12 0.339 0.292 0.189 0.151 0.190 13 0.142 0.073 0.195 0.160 0.203 160.191 0.140 0.148 0.135 0.170 17 0.217 0.174 0.230 0.102 0.196 18 0.2320.287 0.157 0.167 0.219 20 0.128 0.151 0.138 0.067 0.239 21 0.202 NC NC0.214 NC 22 0.176 0.167 0.177 0.138 0.292 23 0.323 0.193 0.184 0.1520.323 25 0.248 0.202 0.133 0.135 0.174 26 0.085 0.107 0.146 0.188 0.317Average 0.20 ± 0.3 0.18 ± 0.04 0.18 ± 0.02 0.15 ± 0.02 0.24 ± 0.04 NC =not calculated

TABLE 31C (AUC_(0-Tmax))/(AUC₀₋₄₈), for Various Compositions in Part 2Lot 1Z Lot 5Z Lot 3Z Lot 6Z (IR) (20%) (25%) (40%) AUC_(0-Tmax)AUC_(0-Tmax) AUC_(0-Tmax) AUC_(0-Tmax) Subject AUC₀₋₄₈ AUC₀₋₄₈ AUC₀₋₄₈AUC₀₋₄₈ 78 0.210 0.187 0.144 0.098 79 0.262 0.253 0.125 0.229 80 0.1910.194 0.156 0.145 81 0.202 0.153 0.097 0.064 83 0.180 0.049 0.225 0.14984 0.363 0.138 0.136 0.144 85 0.242 0.204 0.131 0.078 91 0.141 0.1940.129 0.195 93 0.279 0.181 0.200 0.186 97 0.285 0.248 0.267 0.155 990.206 0.202 0.225 0.192 102 0.182 0.163 0.152 0.127 107 0.215 0.2980.180 0.131 111 NC 0.218 NC NC 112 0.208 0.224 0.199 0.161 113 0.2350.170 NC 0.208 114 NC 0.152 NC 0.126 115 0.200 0.256 0.106 0.115 Average0.23 ± 0.03 0.19 ± 0.03 0.17 ± 0.03 0.15 ± 0.02 NC = not calculated

The present inventors have discovered that the kinetics of amisulpride'sgastrointestinal absorption is uneven and leads to transiently high drugconcentrations at Tmax, and that the kinetics of amisulpridepermeability across the blood-brain barrier appear to be unique amongwhat is known about antipsychotics' brain occupancies. In addition, thepresent inventors have discovered that amisulpride isomers havedurations of brain pharmacodynamics that extend well beyond the plasmapharmacokinetics. Thus in various embodiments, the inventors provide MRdrug formulations with kinetics to reduce the Cmax of the therapeuticagents (85:15 R:S amisulpride) while still achieving the brainoccupancies that provide therapeutic effects.

In addition, measurements of QT interval prolongation were alsoconducted in this study. The subjects were administered a single solidoral dose of a fixed ratio composition of (R)-amisulpride to(S)-amisulpride of 85:15 by weight at total composition amounts of 200mg (170 mg R-amisulpride:30 mg S-amisulpride) in various formulations.Specifically, QT interval measurements for the subjects in this studywere conducted on an IR formulation (Lot 1Z), three modifiedformulations given in a fasted stated (i.e. the formulations of Lot 2Z,Lot 3Z and Lot 4Z), and one modified release formulation given in a fedstate (i.e. formulation of Lot 3Z fed state)

QT interval measurements for the subjects in this study were made bycontinuous 12-lead ECGs recorded with Holter monitors for a minimum of25 hours post-dose. The Holter monitor was attached to the subjectsprior to initiating the continuous recording. The Holter monitor wasstarted approximately 2 to 3 hours prior to dosing and continuedpost-dose. ECGs were extracted from the continuous recording by acentral ECG laboratory from at least 3 pre-dose time-points (−45, −30and −15 minutes) and at 13 post-dose time points, at the followingtimes: 20, 45, 80, 120, 160, 200, 240, 280 minutes (±5 minutes) postdose and at 5.5, 6.5, 7.5, 9, 12 and 24 h (±10 minutes) post dose. Ateach time point, subjects were supine for at least 10 minutes prior toand 5 minutes after the extraction time point. The central ECGlaboratory used an advanced computer-assisted and statistical process toextract ECGs from continuous recordings. During the specified ECGextraction windows, 10-second digital 12-lead ECG tracings wereextracted from continuous recordings by identifying periods ofrecordings with the lowest available heart rate variability and noise.At each time point specified, up to 10 ECG replicates were extracted.All readable cardiac cycles from these ECG replicates were assessed formultiple quality metrics, including beat stability, heart rate changes,noise, and other parameters, and were categorized into high and lowconfidence ranks. All low confidence beats were fully reviewed andadjudicated manually by ECG technicians using pass-fail criteria. Thebeats found acceptable by manual review were included in the analysis.

Baseline data was obtained, respectively, for 14, 13, 16, and 13subjects in treatment periods with Lot 2Z, Lot 4Z, Lot 3Z, and Lot 3Zgiven in a fed state, and from 17 subjects administered the IRformulation of Lot 1Z. Baseline HR and QTcF were within expectations fora healthy adult population with mean baseline HR across treatmentsbetween 60.2 and 61.8 bpm and mean baseline QTcF across treatmentsbetween 402.9 and 414.5 ms. The measured baseline values of heart rate(HR) and QTcF are given in Table 32, where n is the number of subjects,SD is standard deviation, SE is standard error, L 90% CI is the lower90% confidence interval, and U 90% CI is the upper 90% confidenceinterval.

TABLE 32 Baseline Parameters LOT 3Z Parameter Statistics LOT 2Z LOT 4ZLOT 3Z fed state LOT 1Z QTcF (ms) n 14 13 16 13 17 Mean (SD) 411.4(19.83) 407.5 (18.76) 412.7 (19.97) 402.9 (18.81) 414.5 (20.26) SE 5.305.20 4.99 5.22 4.91 L 90% CI 402.03 398.25 403.98 393.57 405.97 U 90% CI420.80 416.79 421.48 412.16 423.12 Median 409.5 403.5 411.0 398.1 408.6HR (bpm) n 14 13 16 13 17 Mean (SD) 61.8 (6.39) 61.4 (6.79) 60.8 (7.96)60.2 (6.57) 60.9 (8.51) SE 1.71 1.88 1.99 1.82 2.06 L 90% CI 58.75 58.0057.34 56.92 57.30 U 90% CI 64.80 64.71 64.32 63.41 64.51 Median 62.060.2 59.3 57.6 57.7

A summary of the observed values for HR and change from baseline, ΔHR,are presented in Table 33, and the observed values for QTcF and changefrom baseline, ΔQTcF, are presented in Table 34. In Tables 33 and 34, SEis standard error, L 90% CI is the lower 90% confidence interval, and U90% CI is the upper 90% confidence interval, Min is the minimum observedvalue, Max the maximum observed value, and n the number of subjects.

Mean change-from-baseline HR (ΔHR) was similar across treatments, exceptfor the Lot 3Z fed state treatment, in which mean ΔHR increasedimmediately after dosing, likely due to the effect of food digestion onHR. In the first 240 minutes after dosing, mean ΔHR on the othertreatments ranged from −1.6 to 3.2 bpm, while mean ΔHR on the Lot 3Z fedstate treatment reached 10.8 bpm at 20 minutes post-dose. From 280minutes through 24 hours post-dose, mean ΔHR ranged from 1.9 to 10.9 bpmacross all treatments, with very similar patterns across treatmentperiods.

Mean change-from-baseline QTcF (ΔQTcF) was largest at 280 minutespost-dose for all treatments, with mean ΔQTcF on Lot 1Z (IR formulation)and Lot 2Z reaching 14.4 and 14.1 ms, respectively.

TABLE 33 Summary of observed values and change-from-baseline values ofHR LOT 2Z LOT 4Z LOT 3Z LOT 3Z LOT 1Z Time Point Parameter Statistics(10%) (15%) (25%) fed state (IR) Baseline HR (bpm) n 14 13 16 13 17 Mean(SD) 61.8 (6.4) 61.4 (6.8) 60.8 (8.0) 60.2 (6.6) 60.9 (8.5) SE 1.71 1.881.99 1.82 2.06 Median 62 60.2 59.3 57.6 57.7 L 90% CI 58.75 58.00 57.3456.92 57.30 U 90% CI 64.80 64.71 64.32 63.41 64.51 Min, Max 51, 76 54,77 51, 76 53, 77 52, 87 20 min Post- HR (bpm) n 14 13 16 13 17 dose Mean(SD) 61.4 (6.0) 61.6 (6.5) 60.3 (7.6) 71.1 (8 5) 59.4 (7.4) SE 1.60 1.811.90 2.36 1.80 Median 61.5 60.2 59.3 70 58.5 L 90% CI 58.60 58.35 56.9366.91 56.23 U 90% CI 64.28 64.81 63.58 75.31 62.53 Min, Max 52, 74 54,78 50, 76 59, 87 47, 78 ΔHR (bpm) n 14 13 16 13 17 Mean (SD) −0.3 (2.9)0.2 (2.3) −0.6 (3.2) 10.9 (4.4) −1.5 (4.4) SE 0.79 0.63 0.81 1.23 1.07Median −0.6 0 −0.1 11.9 −1.1 L 90% CI −1.72 −0.90 −1.98 8.75 −3.39 U 90%CI 1.06 1.35 0.84 13.14 0.33 Min, Max −5, 3 −5, 4 −6, 7 2, 16 −10, 6 45min Post- HR (bpm) n 14 13 16 13 17 dose Mean (SD) 61.3 (6.9) 61.6 (7.1)60.0 (7.1) 68.2 (6.9) 60.6 (7.0) SE 1.84 1.98 1.77 1.91 1.70 Median 6162.4 59.7 68.3 59.9 L 90% CI (8.05 58.03 56.89 64.84 57.67 U 90% CI64.57 65.08 63.10 71.66 63.60 Min, Max 53, 78 53, 79 49, 77 60, 83 48,77 ΔHR (bpm) n 14 13 16 13 17 Mean (SD) −0.5 (3.4) 0.2 (4.5) −0.8 (3.2)8.1 (3.9) −0.3 (4.7) SE 0.90 1.26 0.80 1.07 1.14 Median −1.4 1.4 −0.98.2 0.7 L 90% CI −2.05 −2.04 −2.24 6.18 −2.27 U 90% CI 1.13 2.45 0.569.99 1.72 Min, Max −6, 5 −13, 4 −9, 4 2, 14 −10, 8 80 min Post- HR (bpm)n 14 13 16 13 17 dose Mean (SD) 60.5 (7.1) 59.8 (6.0) 59.6 (8.7) 66.7(6.9) 59.7 (7.6) SE 1.90 1.67 2.17 1.91 1.83 Median 59.4 59.8 59 66.355.9 L 90% CI 57.10 56.84 55.80 63.31 56.47 U 90% CI 63.85 62.80 63.4070.11 62.86 Min, Max 49, 75 52, 74 45, 77 59, 84 50, 77 ΔHR (bpm) n 1413 16 13 17 Mean (SD) −1.3 (2.9) −1.5 (4.2) −1.2 (3.9) 6.5 (3.9) −1.2(4.9) SE 0.77 1.15 0.97 1.07 1.19 Median −2.2 −0.4 −1.6 6.8 −0.1 L 90%CI −2.65 −3.59 −2.93 4.64 −3.33 U 90% CI 0.06 0.52 0.47 8.45 0.85 Min,Max −6, 4 −12, 3 −6, 6 −1, 15 −14, 7 120 min HR (bpm) n 13 13 16 13 17Post-dose Mean (SD) 62.3 (8.4) 62.7 (7.0) 59.6 (8.2) 65.4 (6.4) 60.9(8.4) SE 2.34 1.93 2.06 1.77 2.03 Median 62 61.9 58.4 64 58.8 L 90% CI58.10 59.29 55.94 62.23 57.38 U 90% CI 66.45 66.18 63.16 68.53 64.47Min, Max 51, 79 54, 79 46, 77 58, 81 46, 78 ΔHR (bpm) n 13 13 16 13 17Mean (SD) 0.6 (4.2) 1.4 (4.7) −1.3 (5.3) 5.2 (4.5) 0.0 (4.8) SE 1.161.29 1.32 1.25 1.16 Median 2.2 2.7 −0.5 6.2 0.6 L 90% CI −1.48 −0.92−3.60 2.98 −2.00 U 90% CI 2.64 3.69 1.04 7.45 2.04 Min, Max −8, 6 −13, 5−11, 7 −3, 13 −9, 8 160 min HR (bpm) n 14 13 16 13 17 Post-dose Mean(SD) 63.3 (7.6) 62.5 (8.0) 61.2 (8.4) 64.9 (6.6) 59.9 (7.2) SE 2.03 2.212.09 1.82 1.75 Median 63.4 62.1 59.2 65 58.8 L 90% CI 59.69 58.56 57.5361.63 56.85 U 90% CI 66.88 66.43 64.86 68.12 62.96 Min, Max 52, 78 53,82 52, 77 55, 81 49, 78 ΔHR (bpm) n 14 13 16 13 17 Mean (SD) 1.5 (2.9)1.1 (3.3) 0.4 (4.0) 4.7 (4.8) −1.0 (5.5) SE 0.79 0.93 1.01 1.33 1.34Median 2 0.4 1.1 5.8 −0.1 L 90% CI 0.12 −0.51 −1.40 2.33 −3.35 U 90% CI2.91 2.80 2.13 7.09 1.35 Min, Max −3, 9 −5, 7 −8, 8 −4, 12 −12, 9 200min HR (bpm) n 14 13 16 13 17 Post-dose Mean (SD) 63.9 (6.4) 62.6 (7.0)60.7 (7.3) 64.8 (7.2) 61.9 (8.3) SE 1.70 1.95 1.83 2.00 2.00 Median 64.362.8 59.5 64 61.8 L 90% CI 60.88 59.15 57.50 61.27 58.43 U 90% CI 66.8966.11 63.93 68.39 65.41 Min, Max 53, 74 54, 79 52, 74 56, 82 46, 80 ΔHR(bpm) n 14 13 16 13 17 Mean (SD) 2.1 (2.8) 1.3 (1.8) −0.1 (4.2) 4.7(4.8) 1.0 (5.5) SE 0.76 0.50 1.05 1.32 1.34 Median 2.3 1.4 1.1 5.1 2.5 L90% CI 0.77 0.38 −1.95 2.32 −1.33 U 90% CI 3.45 2.17 1.72 7.02 3.36 Min,Max −3, 8 −1, 4 −7, 9 −1, 16 −10, 10 240 min HR (bpm) n 14 13 16 13 17Post-dose Mean (SD) 64.5 (8.1) 64.5 (7.6) 61.0 (8.2) 64.3 (7.4) 62.2(9.4) SE 2.17 2.10 2.06 2.04 2.28 Median 62.3 63.9 59.4 63.5 60 L 90% CI60.66 60.77 57.39 60.65 58.21 U 90% CI 68.34 68.27 64.61 67.93 66.16Min, Max 53, 83 55, 84 47, 77 55, 83 46, 82 ΔHR (bpm) n 14 13 16 13 17Mean (SD) 2.7 (4.4) 3.2 (3.7) 0.2 (4.3) 4.1 (3.7) 1.3 (5.8) SE 1.18 1.041.09 1.03 1.41 Median 2.4 3.3 1.3 4 1.6 L 90% CI 0.64 1.31 −1.74 2.29−1.18 U 90% CI 4.82 5.01 2.07 5.96 3.74 Min, Max −5, 12 −5, 8 −7, 7 −1,12 −8, 14 280 min HR (bpm) n 14 13 15 13 17 Post-dose Mean (SD) 71.1(9.3) 71.2 (8.1) 70.6 (9.7) 66.4 (7.0) 69.4 (9.9) SE 2.50 2.25 2.50 1.952.41 Median 69.8 70.4 68.3 68.5 70.3 L 90% CI 66.70 67.15 66.19 62.9165.17 U 90% CI 75.54 75.16 74.99 69.85 73.59 Min, Max 53, 88 56, 84 58,91 55, 79 50, 86 ΔHR (bpm) n 14 13 15 13 17 Mean (SD) 9.3 (5.9) 9.8(4.9) 9.2 (7.4) 6.2 (5.6) 8.5 (7.4) SE 1.57 1.35 1.92 1.56 1.80 Median9.9 10.2 9.5 5.2 9.5 L 90% CI 6.57 7.39 5.80 3.44 5.32 U 90% CI 12.1312.22 12.56 8.99 11.62 Min, Max −3, 18 2, 18 −2, 21 −2, 16 −4, 19 5.5 hPost- HR (bpm) n 13 13 16 13 17 dose Mean (SD) 71.1 (6.9) 72.1 (8.0)68.7 (9.8) 69.5 (7.4) 69.5 (8.3) SE 1.91 2.22 2.44 2.05 2.02 Median 68.471.2 68.8 68.7 70.8 L 90% CI 67.73 68.20 64.44 65.81 65.94 U 90% CI74.53 76.10 72.99 73.11 73.01 Min, Max 63, 84 56, 84 53, 84 60, 85 55,85 n 13 13 16 13 17 ΔHR (bpm) Mean (SD) 9.2 (4.8) 10.8 (6.0) 7.9 (6.7)9.3 (6.1) 8.6 (7.2) SE 1.34 1.67 1.68 1.69 1.75 Median 8.9 11 6.5 5.98.5 L 90% CI 6.84 7.82 4.94 6.28 5.51 U 90% CI 11.61 13.77 10.82 12.3111.62 Min, Max 4, 21 −0, 24 −1, 23 2, 21 −10, 21 n 14 13 15 13 17 6.5 hPost- HR (bpm) Mean (SD) 72.0 (8.4) 72.1 (10.1) 70.9 (9.2) 70.6 (8.1)70.6 (8.7) dose SE 2.25 2.80 2.36 2.24 2.12 Median 72.4 68.9 70 71.471.2 L 90% CI 68.03 67.15 66.72 66.58 66.87 U 90% CI 76.00 77.11 75.0474.56 74.26 Min, Max 59, 89 59, 89 53, 85 59, 90 54, 88 n 14 13 15 13 17ΔHR (bpm) Mean (SD) 10.2 (3.8) 10.8 (6.6) 9.5 (6.1) 10.4 (5.9) 9.7 (7.1)SE 1.03 1.82 1.57 1.63 1.72 Median 9.6 8.3 9.3 9.3 11.6 L 90% CI 8.437.52 6.72 7.50 6.65 U 90% CI 12.06 14.03 12.23 13.32 12.66 Min, Max 6,19 4, 26 2, 23 2, 20 −6, 20 n 14 13 16 13 17 7.5 h Post- HR (bpm) Mean(SD) 70.0 (10.1) 70.9 (10.7) 66.9 (9.6) 66.3 (8.8) 68.2 (9.9) dose SE2.69 2.96 2.40 2.44 2.41 Median 67.8 70.5 64.7 66 67.8 L 90% CI 65.2265.67 62.67 61.94 63.98 U 90% CI 74.73 76.23 71.09 70.63 72.41 Min, Max55, 92 57, 87 53, 86 57, 87 50, 89 n 14 13 16 13 17 ΔHR (bpm) Mean (SD)8.2 (6.1) 9.6 (6.0) 6.1 (6.7) 6.1 (6.5) 7.3 (6.5) SE 1.62 1.66 1.67 1.811.57 Median 7.6 8.8 3.7 4.3 8.4 L 90% CI 5.33 6.64 3.12 2.90 4.55 U 90%CI 11.07 12.55 8.98 9.34 10.02 Min, Max −1, 19 3, 23 −4, 21 −4, 16 −7,17 n 14 13 16 13 17 9 h Post- HR (bpm) Mean (SD) 66.9 (8.4) 66.6 (8.7)63.2 (10.2) 62.2 (7.5) 65.0 (10.1) dose SE 2.25 2.40 2.54 2.07 2.45Median 66.1 64.3 60.4 61.8 63.5 L 90% CI 62.93 62.34 58.77 58.49 60.71 U90% CI 70.88 70.90 67.68 65.88 69.26 Min, Max 55, 84 58, 85 51, 86 52,81 48, 88 n 14 13 16 13 17 ΔHR (bpm) Mean (SD) 5.1 (4.4) 5.3 (4.4) 2.4(7.1) 2.0 (4.0) 4.1 (6.2) SE 1.16 1.23 1.78 1.11 1.50 Median 4.4 3.6 1.43.1 3.4 L 90% CI 3.07 3.07 −0.73 0.04 1.46 U 90% CI 7.19 7.46 5.52 4.006.70 Min, Max −1, 13 −1, 16 −10, 15 −3, 10 −7, 13 n 14 13 15 13 17 12 hPost- HR (bpm) Mean (SD) 69.3 (8.0) 69.7 (9.5) 66.9 (8.2) 68.1 (7.0)67.0 (9.7) dose SE 2.13 2.65 2.12 1.95 2.36 Median 67.9 69 66.7 67.468.2 L 90% CI 65.56 65.01 63.21 64.67 62.92 U 90% CI 73.13 74.45 70.6971.62 71.14 Min, Max 58, 85 55, 84 55, 80 59, 80 51, 92 n 14 13 15 13 17ΔHR (bpm) Mean (SD) 7.6 (3.7) 8.4 (5.4) 6.5 (4.9) 8.0 (4.0) 6.1 (5.0) SE1.00 1.51 1.27 1.10 1.22 Median 7.7 8.4 6.7 8.5 5.5 L 90% CI 5.81 5.684.24 6.02 (3.99 U 90% CI 9.34 11.07 8.72 9.94 8.26 Min, Max 1, 14 1, 18−3, 18 2, 15 −3, 15 n 11 13 16 13 17 24 h Post- HR (bpm) Mean (SD) 67.0(8.6) 68.5 (9.0) 65.2 (6.8) 67.3 (7.2) 66.9 (10.6) dose SE 2.60 2.501.70 2.00 2.56 Median 65.7 69.1 63.8 66.1 65.1 L 90% CI 62.26 64.0362.26 63.75 62.38 U 90% CI 71.68 72.96 68.21 70.89 71.33 Min, Max 59, 8352, 91 54, 80 58, 85 49, 91 n 11 13 16 13 17 ΔHR (bpm) Mean (SD) 4.4(5.6) 7.1 (5.8) 4.4 (6.0) 7.2 (5.4) 6.0 (7.9) SE 1.67 1.60 1.50 1.491.92 Median 4.6 5.1 4.1 7.4 6.5 L 90% CI 1.36 4.2 1.78 4.49 2.60 U 90%CI 7.43 10.00 7.03 9.82 9.30 Min, Max −4, 14 −1, 17 −6, 14 −4, 17 −12,18

TABLE 34 Summary of observed values and change-from-baseline values ofQTcF LOT 2Z LOT 4Z LOT 3Z LOT 3Z Time Point Parameter Statistics (10%)(15%) (25%) fed state LOT 1Z (IR) Baseline QTcF (ms) n 14 13 16 13 17Mean (SD) 411.4 (19.8) 407.5 (18.8) 412.7 (20.0) 402.9 (18.8) 414.5(20.3) SE 5.30 5.20 4.99 5.22 4.91 Median 409.5 403.5 411 398.1 408.6 L90% CI 402.03 398.25 403.98 393.57 405.97 U 90% CI 420.80 416.79 421.48412.16 423.12 Min, Max 380, 447 381, 445 375, 444 381, 443 381, 448 20min Post- QTcF (ms) n 14 13 16 13 17 dose Mean (SD) 413.1 (20.4) 406.3(19.9) 411.3 (22.2) 401.9 (18.2) 414.0 (21.7) SE 5.44 5.52 5.55 5.045.25 Median 410.6 402.1 409.8 397.7 405.7 L 90% CI 403.44 396.47 401.56392.94 404.78 U 90% CI 422.70 416.13 421.03 410.92 423.12 Min, Max 381,452 377, 447 378, 453 382, 446 382, 450 ΔQTcF ms n 14 13 16 13 17 Mean(SD) 1.7 (5.0) −1.2 (2.9) −1.4 (5.8) −0.9 (4.3) −0.6 (3.7) SE 1.33 0.791.44 1.20 0.90 Median 1 −1.3 −0.1 −0.4 −0.9 L 90% CI −0.71 −2.63 −3.97−3.08 −2.16 U 90% CI 4.02 0.19 1.09 1.21 0.98 Min, Max −5, 11 −6, 3 −13,12 −10, 6 −7, 8 45 min Post- QTcF (ms) n 14 13 16 13 17 dose Mean (SD)412.7 (18.9) 407.0 (19.9) 412.7 (21.2) 399.7 (19.2) 416.0 (19.1) SE 5.065.51 5.31 5.32 4.63 Median 412.9 400.5 409.8 395.2 414.2 L 90% CI 403.73397.16 403.36 390.21 407.95 U 90% CI 421.66 416.80 421.98 409.18 424.11Min, Max 384, 445 375, 451 381, 449 374, 443 378, 454 ΔQTcF (ms) n 14 1316 13 17 Mean (SD) 1.3 (4.1) −0.5 (3.4) −0.1 (3.9) −3.2 (3.6) 1.5 (4.7)SE 1.10 0.95 0.98 0.99 1.14 Median 0.2 −1.3 −1.5 −2.9 2.9 L 90% CI −0.67−2.23 −1.79 −4.93 −0.49 U 90% CI 3.24 1.16 1.67 −1.41 3.47 Min, Max −5,9 −6, 5 −5, 8 −10, 4 −9, 8 80 min Post- QTcF (ms) n 14 13 16 13 17 doseMean (SD) 415.5 (20.1) 409.4 (20.0) 414.9 (21.6) 396.9 (19.2) 420.1(21.4) SE 5.38 5.55 5.41 5.32 5.20 Median 414.1 404.6 413.6 395.9 417.9L 90% CI 405.95 399.48 405.45 387.38 410.98 U 90% CI 425.01 419.25424.43 406.34 429.13 Min, Max 385, 447 380, 454 384, 453 372, 443 381,456 ΔQTcF (ms) n 14 13 16 13 17 Mean (SD) 4.1 (4.1) 1.8 (3.0) 2.2 (4.6)−6.0 (5.6) 5.5 (4.1) SE 1.10 0.84 1.16 1.55 1.00 Median 4.8 1.1 1.7 −5.65.4 L 90% CI 2.11 0.35 0.18 −8.76 3.76 U 90% CI 6.02 3.34 4.24 −3.247.26 Min, Max −2, 13 −2, 9 −5, 12 −17, 0 −1, 13 120 min QTcF (ms) n 1313 16 13 17 Post-dose Mean (SD) 416.0 (22.9) 408.9 (19.1) 414.2 (21.7)397.2 (19.1) 421.7 (21.4) SE 6.36 5.30 5.42 5.28 5.18 Median 416.1 402.9412.6 389.7 431 L 90% CI 404.68 399.48 404.64 387.78 412.62 U 90% CI427.34 418.38 423.66 406.61 430.72 Min, Max 385, 454 379, 450 382, 450375, 444 380, 457 ΔQTcF (ms) n 13 13 16 13 17 Mean (SD) 5.9 (6.6) 1.4(4.1) 1.4 (4.1) −5.7 (5.2) 7.1 (8.1) SE 1.84 1.14 1.02 1.44 1.96 Median3.3 0 1.2 −4.6 6.3 L 90% CI 2.66 −0.62 −0.37 −8.24 3.71 U 90% CI 9.233.43 3.21 −3.11 10.54 Min, Max −1, 21 −6, 7 −5, 11 −16, 4 −4, 33 160 minQTcF (ms) n 14 13 16 13 17 Post-dose Mean (SD) 420.3 (23.4) 408.3 (17.8)417.9 (24.0) 396.7 (18.5) 425.2 (21.8) SE 6.24 4.95 6.00 5.13 5.28Median 416.3 404.1 418.9 389.8 427.6 L 90% CI 409.20 399.48 407.40387.55 416.03 U 90% CI 431.30 417.12 428.45 405.85 434.45 Min, Max 386,458 378, 441 382, 456 376, 439 383, 464 ΔQTcF(ms) n 14 13 16 13 17 Mean(SD) 8.8 (8.6) 0.8 (4.6) 5.2 (5.9) −6.2 (4.8) 10.7 (12.3) SE 2.29 1.271.48 1.34 2.97 Median 6.3 0.6 4.8 −5.7 7.6 L 90% CI 4.78 −1.49 2.61−8.55 5.51 U 90% CI 12.90 3.04 7.78 −3.78 15.89 Min, Max −2, 27 −8, 8−6, 18 −17, 2 −6, 38 200 min QTcF (ms) n 14 13 16 13 17 Post-dose Mean(SD) 423.9 (24.1) 411.8 (21.8) 421.3 (25.1) 398.5 (18.4) 425.4 (22.1) SE6.44 6.05 6.27 5.10 5.35 Median 423 409.9 421.4 389.9 421.8 L 90% CI412.48 401.02 410.35 389.39 416.04 U 90% CI 435.28 422.60 432.33 407.56434.72 Min, Max 386, 476 378, 458 387, 474 379, 441 384, 469 ΔQTcF (ms)n 14 13 16 13 17 Mean (SD) 12.5 (11.3) 4.3 (7.2) 8.6 (8.8) −4.4 (5.9)10.8 (9.2) SE 3.02 1.99 2.19 1.63 2.24 Median 7.6 3.1 7.8 −2.9 9.1 L 90%CI 7.12 0.74 4.77 −7.30 6.93 U 90% CI 17.82 7.84 12.45 −1.48 14.74 Min,Max −2, 34 −4, 22 −5, 36 −18, 4 −3, 37 240 min QTcF (ms) n 14 13 16 1317 Post-dose Mean (SD) 421.5 (23.3) 413.2 (24.1) 418.6 (22.5) 399.6(19.6) 423.3 (20.1) SE 6.21 6.68 5.63 5.44 4.86 Median 418 407.1 418.1396.9 424.6 L 90% CI 410.45 401.25 408.75 389.89 414.79 U 90% CI 432.46425.06 428.48 409.27 431.77 Min, Max 390, 475 377, 462 389, 462 375, 444384, 456 ΔQTcF (ms) n 14 13 16 13 17 Mean (SD) 10.0 (7.4) 5.6 (11.1) 5.9(6.2) −3.3 (5.5) 8.7 (7.9) SE 1.97 3.08 1.54 1.54 1.92 Median 7.9 5.54.5 −1.7 8.5 L 90% CI 6.57 (0.14 (3.19 −6.02 5.38 U 90% CI 13.53 11.138.58 −0.54 12.09 Min, Max 0, 28 −6, 35 −0, 25 −15, 4 −5, 25 280 min QTcF(ms) n 14 13 15 13 17 Post-dose Mean (SD) 425.4 (23.5) 415.1 (21.5)423.2 (26.6) 404.2 (20.7) 429.0 (23.9) SE 6.28 5.96 6.87 5.75 5.80Median 424.2 406.1 419.7 398.6 428 L 90% CI 414.27 404.49 411.10 393.94418.88 U 90% CI 436.50 425.74 435.29 414.45 439.13 Min, Max 390, 479383, 453 389, 481 378, 454 387, 470 ΔQTcF (ms) n 14 13 15 13 17 Mean(SD) 14.0 (10.6) 7.6 (11.9) 10.9 (11.2) 1.3 (8.8) 14.5 (10.4) SE 2.853.31 2.89 2.44 2.53 Median 13 4.4 11.2 2.7 15.1 L 90% CI 8.93 1.70 5.78−3.01 10.05 U 90% CI 19.01 13.49 15.97 5.67 18.87 Min, Max −6, 32 −12,30 −7, 43 −15, 15 −7, 35 5.5 h Post- QTcF (ms) n 13 13 16 13 17 doseMean (SD) 420.4 (22.1) 408.3 (18.2) 416.1 (28.2) 403.7 (17.8) 420.8(25.2) SE 6.12 5.06 7.04 4.94 6.11 Median 417.1 405.8 409.1 396.1 419 L90% CI 409.53 399.30 403.77 394.88 410.10 U 90% CI 431.34 417.34 428.45412.49 431.43 Min, Max 385, 475 377, 439 377, 478 385, 444 380, 467ΔQTcF (ms) n 13 13 16 13 17 Mean (SD) 6.6 (10.2) 0.8 (11.1) 3.4 (13.0)0.8 (7.5) 6.2 (10.2) SE 2.83 3.07 3.24 2.09 2.46 Median 8.2 4.2 1.6 3.34.3 L 90% CI 1.58 −4.67 −2.30 −2.90 1.92 U 90% CI 11.66 6.26 9.07 4.5410.52 Min, Max −9, 27 −26, 13 −18, 40 −12, 10 −15, 24 6.5 h Post- QTcF(ms) n 14 13 15 13 17 dose Mean (SD) 414.1 (24.2) 405.2 (16.8) 414.9(25.3) 403.2 (19.4) 415.0 (21.7) SE 6.46 4.66 6.52 5.38 5.27 Median411.1 403.3 407.6 398.5 413.8 L 90% CI 402.65 396.93 403.37 393.65405.79 U 90% CI 425.53 413.53 426.36 412.82 424.18 Min, Max 379, 469379, 428 383, 473 384, 454 380, 452 ΔQTcF (ms) n 14 13 15 13 17 Mean(SD) 2.7 (8.5) −2.3 (7.1) 2.5 (10.3) 0.4 (6.9) 0.4 (6.5) SE 2.27 1.972.66 1.90 1.57 Median 0.5 −2.3 −1 −2 −1.1 L 90% CI −1.35 −5.79 −2.15−3.03 −2.30 U 90% CI 6.70 1.21 7.24 3.76 3.18 Min, Max −8, 22 −17, 6 −8,36 −9, 12 −11, 12 7.5 h Post- QTcF (ms) n 14 13 16 13 17 dose Mean (SD)410.1 (21.7) 403.3 (15.9) 410.0 (21.7) 399.3 (18.5) 412.9 (20.5) SE 5.804.42 5.42 5.13 4.98 Median 408.5 402.5 405.8 396 409.1 L 90% CI 399.79395.43 400.49 390.14 404.22 U 90% CI 420.32 411.18 419.49 408.44 421.61Min, Max 372, 448 376, 425 376, 449 379, 442 380, 455 ΔQTcF (ms) n 14 1316 13 17 Mean (SD) −1.4 (8.4) −4.2 (9.1) −2.7 (6.8) −3.6 (6.6) −1.6(8.4) SE 2.26 2.51 1.69 1.83 2.04 Median −1.5 −4.2 −3.1 −3.5 −1.5 L 90%CI −5.36 −8.70 −5.70 −6.85 −5.19 U 90% CI 2.64 0.26 0.23 −0.31 1.93 Min,Max −15, 14 −20, 10 −14, 11 −17, 10 −18, 11 9 h Post- QTcF (ms) n 14 1316 13 17 dose Mean (SD) 412.0 (23.5) 406.6 (17.5) 410.9 (21.3) 400.8(18.2) 413.8 (20.4) SE 6.28 4.86 5.32 5.04 4.95 Median 406 405.1 410.3392.8 418.7 L 90% CI 400.83 397.98 401.56 391.85 405.11 U 90% CI 423.08415.30 420.22 409.80 422.41 Min, Max 380, 469 378, 437 379, 449 381, 437380, 455 ΔQTcF (ms) n 14 13 16 13 17 Mean (SD) 0.5 (10.2) −0.9 (8.5)−1.8 (5.8) −2.0 (5.7) −0.8 (5.6) SE 2.72 2.36 1.45 1.59 1.36 Median −0.30.7 −1.5 −2.8 −1 L 90% CI −4.27 −5.09 −4.38 −4.87 −3.15 U 90% CI 5.363.34 0.69 0.80 1.59 Min, Max −14, 28 −18, 14 −14, 9 −11, 6 −11, 11 12 hPost- QTcF (ms) n 14 13 15 13 17 dose Mean (SD) 411.6 (22.0) 410.9(22.3) 411.1 (20.3) 400.7 (18.7) 412.5 (19.5) SE 5.87 6.19 5.25 5.194.73 Median 410.9 407.1 413.5 401.9 414.3 L 90% CI 401.20 399.89 401.89391.44 (404.19 U 90% CI 421.99 421.97 420.38 409.93 420.71 Min, Max 376,459 379, 460 380, 448 376, 443 375, 445 ΔQTcF (ms) n 14 13 15 13 17 Mean(SD) 0.2 (8.8) 3.4 (8.3) −2.5 (6.3) −2.2 (8.1) −2.1 (7.2) SE 2.34 2.301.64 2.25 1.75 Median −2.1 1.4 −3 −2.3 −2.2 L 90% CI −3.96 −0.68 −5.34−6.18 −5.15 U 90% CI 4.33 7.50 0.43 1.83 0.97 Min, Max −10, 18 −12, 21−12, 8 −16, 16 −14, 10 24 h Post- QTcF (ms) n 11 13 16 13 17 dose Mean(SD) 406.1 (21.5) 403.9 (18.3) 408.1 (22.5) 398.0 (17.0) 407.8 (20.6) SE6.49 5.08 5.62 4.72 5.00 Median 406.8 403 403.5 392.2 399.4 L 90% CI394.31 394.86 398.29 389.55 399.10 U 90% CI 417.82 412.96 417.98 406.40416.57 Min, Max 377, 442 378, 436 378, 455 376, 434 378, 447 ΔQTcF (ms)n 11 13 16 13 17 Mean (SD) −3.3 (7.8) −3.6 (3.3) −4.6 (10.1) −4.9 (5.5)−6.7 (7.8) SE 2.35 0.91 2.52 1.52 1.89 Median −5.7 −2.9 −5.2 −6.5 −6.9 L90% CI −7.59 −5.23 −9.01 −7.60 −10.01 U 90% CI 0.94 −1.99 −0.17 −2.17−3.41 Min, Max −12, 17 −9, 2 −30, 13 −13, 6 −25, 6

The effect of amisulpride (enantiomers and total) onchange-from-baseline QTcF and heart rate (ΔQTcF and ΔHR) was evaluatedbased on a linear mixed-effects model at each nominal post-dosing timepoint (“by-time point analysis”) using the intersection union test. Inthe concentration-QTc analysis (primary analysis), the full modelincluded ΔQTcF as the dependent variable, time-matched plasmaconcentrations of R- and S- and total amisulpride enantiomers as theexplanatory variates, centered baseline QTcF (i.e., baseline QTcF forindividual subject subtracting the population mean baseline QTcF for allsubjects) as an additional covariate, a fixed intercept, and randomeffect for both intercept and slopes per subject, when applicable. Apre-specified model selection procedure was then performed to choose aprimary model from among the full model and reduced models from possiblefirst order combinations (without quadratic and interaction terms) amongthese 3 analytes of concentrations of R- and S-enantiomers and totalamisulpride (including models with only 1 analyte and with any 2analytes). In the concentration-QTc analysis, all models from thepossible first order combinations among the 3 analytes (S-amisulpride,R-amisulpride, and total of amisulpride enantiomers) were considered.The total of amisulpride enantiomers (total amisulpride) was used as theprimary model since the concentration value of total amisulprideenantiomers is the sum of S-amisulpride and R-amisulpride, and the 2concentrations of S- and R- were observed to be highly correlated.

This analysis of the observations yielded an estimated population slopeof the concentration-QTc relationship of 0.031 ms per ng/mL (90% CI:0.0257 to 0.0369) for total amisulpride with an intercept of −2.3 ms(90% CI: −4.88 to 0.27). The slope for the relationship was found to bestatistically significant at the 0.1 level, while the intercept was not.Table 35 presents the results of this analysis, where SE is standarderror, df degrees of freedom, and CI confidence interval.

TABLE 35 Linear mixed-effects total amisulpride concentration-QTcrelationship model parameters determined form experimental dataParameter Value SE df t-Value P Value 90% CI Intercept (ms) −2.31 1.41519.6 −1.63 0.1355 −4.881, 0.269 Total Amisulpride Slope 0.031 0.0032 17.09.71 <0.0001 0.0257, 0.0369 (ms per ng/mL) Centered Baseline Effect−0.23 0.0394 100.1 −5.79 <0.0001 −0.293, −0.162 (ms)

The observations and a linear mixed-effects model parameters derivedtherefrom was used to estimate the ΔQTcF at the observed Cmax of theformulation Lots studied. This data is presented in Table 36 and showsthe significant reduction in ΔQTcF for various modified releaseformulations of amisulpride provided herein compared to a comparableimmediate release formulation. For example, the formulation of 4Z showeda reduction in ΔQTcF relative to Lot 1Z (IR) of about 45% at Cmaxrelative to the IR formulation. The formulation of Lot 3Z, administeredin the fed state, showed a reduction in in ΔQTcF relative to Lot 1Z (IR)of about 55% at Cmax relative to the IR formulation; and Lot 3Z,administered in the fasted state, showed a reduction in in ΔQTcFrelative to Lot 1Z (IR) of about 60% at Cmax relative to the IRformulation. As important as the relative reduction, Lots 3Z and 4Zshowed a ΔQTcF prolongation (relative to baseline) of less than 8 ms,and for Lot 3Z less than 6 ms.

TABLE 36 Estimated ΔQTcF at observed geometric mean Cmax Geometric MeanC_(max) (ng/mL) ΔQTcF (ms) Treatment (90% CI) of total amisulpride (90%CI) LOT 2Z (10%) 454.8 (347.64; 595.10) 11.94 (9.10, 14.78) LOT 4Z (15%)301.9 (224.05; 406.81) 7.15 (4.65, 9.65) LOT 3Z (25%) 236.0 (184.86;301.33) 5.09 (2.66, 7.52) LOT 3Z (25%) 260.3 (217.85; 311.01) 5.85(3.40, 8.30) fed state LOT 1Z (IR) 493.3 (400.32; 607.87)  13.15 (10.19,16.11)

TABLE 37 ΔQTcF (max) (IR-MR) (msec) and ±90% Confidence Interval (CI) ofdata plotted in FIG. 23 Average ΔQTcF (max) 90% CI 90% CI Subjects(IR-MR) (msec) Lower Upper Parts 1 & 2 8.21 4.21 12.2 Part 1 6.99 1.0612.9 Part 2 9.93 4.05 15.8

Example 7B: Human Clinical Studies (MAD/PET Imaging)

The therapeutic effects of amisulpride enantiomers occur by directinteractions with dopamine D2 and serotonin 5-HT7 receptors in thebrain. However, measuring directly drug concentration in the brain isnot feasible. Dopamine D2 receptor occupancy by Positron EmissionTomography (PET) in human subjects was used in this study as a surrogateto measure the magnitude of effect of amisulpride in the brain, asbinding to a pharmacological target, relative to the plasmapharmacokinetics measured directly by collecting plasma samples overtime post administration.

In these human clinical studies, single solid oral doses of a fixedratio composition of (R)-amisulpride to (S)-amisulpride of 85:15 byweight were administered to healthy volunteers at total compositionamounts of 200 mg (170 mg R-amisulpride:30 mg S-amisulpride) and 400 mg(340 mg R-amisulpride:60 mg S-amisulpride). Two formulations and twodosing regimens were studied, an IR formulation comprising 200 mg of API(substantially in accord with Lot 1Z of Table 25), and a 25% extendedrelease agent formulation comprising 200 mg of API (substantially inaccord with Lot 3Z of TABLE 24A), studied in two dosage regimens, a 1tablet/day regimen and a 2 tablets/day regimen (i.e. for a total of 400mg of API per day).

Subjects in this study were divided into five cohorts and received 7doses of a given formulation in a once per day dosage regimen.Specifically, subjects received either a 200 mg or 400 mg total dailydose of API once per day formulated as either an immediate release (IR)or modified release formulation, over a period of 7 days with each doseapproximately 24 hours apart.

Day 1 of the study was defined as the day upon which a subject receivedthe first dose of any formulation used in the study. The first cohortcomprised 19 subjects randomly assigned to receive the IR formulationonce daily for a total daily dose of either 200 mg API (n=9) or 400 mgAPI (n=10). Cohorts 2-5 comprised 18 subjects total, and each subjectreceived a modified release formulation comprising 200 mg of API(substantially in accord with Lot 3Z of Table 24A), in one of two dosageregimens, in a total once daily dose of either 200 mg (n=8) API or 400mg (n=10) API.

A summary of the parameters and protocols used in the PET study of thisexample are provided in Table 38 and are further described in theaccompanying text below. Prior to dosing, all subjects received astructural brain T1-weighted high resolution magnetic resonance imaging(MRI) scan and a baseline PET scan. The MRI scan of a subject was usedfor anatomical co-registration with their respective PET scan images forthe image analysis. The PET scans of this study utilized[¹¹C]-propyl-hexahydro-naphtho-oxazin (11C—PHNO) as the imaging ligandand up to 0.3 μg/kg of the imaging ligand was administered intravenouslyas a single bolus injection before the start of a PET scan.

TABLE 38 Summary of PET Imaging Study Parameters and Protocols ImagingLigand: [¹¹C]-propyl-hexahydro-naphtho-oxazin (11C—PHNO) Administration:up to 0.3 μg/kg of the imaging ligand, single bolus intravenousinjection before the start of a PET scan. Specific activities rangedfrom 17-35 Gbq/μmol (mean = 24.6 Gbq/μmol, SD = 5.9 GBq/μmol) Timing ofScan: 27.5 h ± 1 h after a given dose Instrumentation: Siemens PET/CTHi-Rez Biograph 6 scanner, or Siemens PET/CT Biograph 6 TruePoint withTrueV scanner Data Acquisition dynamic emission Sampling Type:Acquisition 90 minute duration and frame durations of 8 × 15 s,Duration: 3 × 60 s, 5 × 120 s, 5 × 300 s, 5 × 600 s Image Fourierrebinning and 2D filtered discrete inverse Processing/ Fourier transformalgorithm with 5 mm isotropic Reconstruction: Gaussian filter on a 128 ×128 matrix with 2.6 zoom giving 2 mm isotropic voxels Correctionsattenuation, randoms, scatter (applied for): D2 Occupancy Determination:$\quad\begin{matrix}{{Regional}\mspace{14mu} {estimate}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {binding}\mspace{14mu} {potential}\mspace{14mu} {relative}} \\{{to}\mspace{14mu} {the}\mspace{14mu} {non}\text{-}{displaceable}\mspace{14mu} {component}\mspace{14mu} \left( {BP}_{ND} \right)\text{:}} \\{{\Delta \; {BP}_{ND}} = {100\; \times \; \left( {1 - \frac{{BP}_{ND}^{{post}\text{-}{dose}}}{{BP}_{ND}^{baeeline}}} \right)\text{..}}}\end{matrix}$ Quantitative MIAKAT software package (version 4.2.6.1),Analysis: simplified reference tissue model (SRTM) Reference CerebellumRegion: Primary Brain dorsal caudate, dorsal putamen Regions for D2Occupancy: Primary Brain substantia nigra Region for D3 Occupancy: BrainRegions ventral striatum, globus pallidus, thalamus for mixed D2/D3Occupancy:

In this study, subjects received two to four PET scans: thirty threesubjects received 4 PET scans, 2 subjects received three PET scans and 2subjects received 2 PET scans. Of the 33 subjects receiving four PETscans, 28 subjects received scans according to the planned schedule: (1)an initial baseline PET scan, (2) a PET scan conducted 27.5 h±1 hfollowing the first dose (i.e. on Day 2), (3) a PET scan conducted 27.5h±1 h following the seventh, and last, dose (i.e. on Day 8), and (4) PETscan conducted approximately 5-7 days after the last dose. The PET scansof Day 2 of the study were conducted before administration of the seconddose, and the second dose was administered within 2 hours aftercompletion of the PET scan. Some subjects did not complete the full setof planned scans or did not have them at the planned timepoints due toradiochemistry issues.

Prior to administration of 11C—PHNO and initiation of the post dose PETscans, venous blood samples were taken from each subject to determineblood plasma concentrations of amisulpride (R-, S- and totalamisulpride).

During the dosing portion of the study subjects resided in the clinicalunit and were admitted the day before the receiving the first dose anddischarged on Day 9, i.e. 48 hours post final dose. On the night beforeDay 1 and Day 7, subjects were provided meals but were required torefrain from all food and drink (except water) for ≥8 hours prior todosing. A light snack was provided upon waking, no later than 2 hoursprior to dosing, on Day 1 and Day 7. Lunch was provided at approximately4 hours post-dose, and an evening meal at approximately 10 hourspost-dose and an evening snack at approximately 14 hours post-dose.Subjects were discharged from the clinical unit on Day 9, and returnedon Day 11 or 12 for the final PET scan.

PET experiments were conducted using 11C—PHNO. [¹¹C]—PHNO is formed insitu by the reaction of [¹¹C]-propionyl chloride with the PET precursordespropyl-PHNO. GMP grade precursor was supplied by ABX withspecification set to >95% for purity (as measured by HPLC). [¹¹C]—PHNOwas purified by solid phase extraction and reformulated in a solution of10% ethanol in normal saline. Specific activities delivered ranged from7.5-48.5 GBq/μmol (mean: 25.2 GBq/μmol, SD: 8.0 GBq/μmol). Radiochemicalpurity was calculated as 100% for all scans.

All dynamic [¹¹C]—PHNO PET scans were acquired on Siemens PET/CTscanners (two similar scanners were used: Hi-Rez Biograph 6 and Biograph6 TruePoint with TrueV, Siemens Healthcare, Erlangen, Germany). Alow-dose CT scan was performed immediately before each PET study inorder to estimate attenuation. Following intravenous bolus injection ofthe radiotracer ([¹¹C]—PHNO), dynamic emission data were acquired for 90minutes (frame durations: 8×15 s, 3×60 s, 5×120 s, 5×300 s, 5×600 s).The dynamic images were reconstructed using Fourier rebinning and a 2Dfiltered discrete inverse Fourier transform algorithm with 5 mmisotropic Gaussian filter on a 128×128 matrix with 2.6 zoom giving 2 mmisotropic voxels. Corrections were applied for attenuation, randoms andscatter.

Dopamine D2 receptor occupancy was calculated for each PET scan viaregional estimate of the binding potential relative to thenon-displaceable component (BPND). Quantitative analysis of PET imageswas performed using the simplified reference tissue model (SRTM) withthe cerebellum serving as the reference region. Primary brain regionsconsidered for D2 receptor occupancy were the dorsal caudate anddorsalputamen. D3 receptor occupancy was assessed using substantianigra. Ventral striatum, globus pallidus, and thalamus were alsoselected to include regions of mixed D2/D3 receptor expression.

Following repeated dosing, the immediate release (IR) and modifiedrelease D2 receptor occupancies were very similar to each other, and tothe single dose IR values. At the final (washout) scans in this study,the D2 signal had returned to baseline values. The D₃ data were markedlymore variable, and showed a decrease in BPND that persisted to thewashout scan.

The following formula was used to determine the dopamine D2 receptoroccupancy based upon D2 receptor occupancy in the dorsal caudate anddorsal putamen

${\Delta BP_{ND}} = {100 \times \left( {1 - \frac{BP_{ND}^{{post} - {dose}}}{BP_{ND}^{baeeline}}} \right)}$

D3 and mixed D2/D3 receptor occupancy was not used to determine D2receptor occupancy.

TABLE 39A Various PK Parameters by Subject for Subjects who wereAdministered a Modified Release Tablet Formulation Substantially Similarto Lot 3Z in Example 7B Total Daily Dose Tmax Cmax AUC₀₋₂₄ (mg) DaySubject (hr) (ng/mL) (hr*ng/mL) 200 1 320 3.67 492 2110 200 1 321 4 2261530 200 1 326 4 371 1550 200 1 327 4 135 838 200 1 328 6.5 118 986 2001 329 5.5 86.8 1070 200 1 332 3.67 179 1080 200 1 333 5.5 64.1 745 200 1336 4 279 1860 200 1 337 5.5 183 1320 200 3 320 5 295 NC 200 3 321 5 395NC 200 3 326 4 683 NC 200 3 327 6 197 NC 200 3 328 6 139 NC 200 3 3292.67 123 NC 200 3 332 8 93.9 NC 200 3 333 2 164 NC 200 3 336 4 279 NC200 3 337 6 264 NC 200 7 320 5 177 1530 200 7 321 3 187 2300 200 7 3284.33 411 2500 200 7 326 4.33 510 2580 200 7 327 4.33 205 2340 200 7 3294 208 2060 200 7 332 4.67 318 3490 200 7 333 4 222 1640 200 7 336 4 2352320 200 7 337 5.5 619 3400 400 1 322 4.33 101 1700 400 1 323 5.5 7174230 400 1 324 5 164 1220 400 1 325 5.5 757 3910 400 1 330 5.5 1080 3440400 1 331 3 535 5020 400 1 334 5 293 2780 400 1 335 4 247 1540 400 3 3225 731 NC 400 3 323 2 312 NC 400 3 324 6 438 NC 400 3 325 6 785 NC 400 3330 5 251 NC 400 3 331 5 527 NC 400 3 334 4 566 NC 400 3 335 2.67 559 NC400 7 322 4 1040 6130 400 7 323 3.67 601 5460 400 7 324 4.33 166 2560400 7 325 6 1040 7950 400 7 330 5.5 505 3120 400 7 331 4.33 1040 7800400 7 334 2.67 955 10800 400 7 335 4 411 3450 NC = not calculated

TABLE 39B Various PK Parameters by Subject for Subject who wereAdministered an Immediate Release Tablet Formulation SubstantiallySimilar to Lot 1Z in Example 7B Total Daily Dose Tmax Cmax AUC₀₋₂₄ (mg)Day Subject (hr) (ng/mL) (hr*ng/mL) 200 1 301 4 190 1520 200 1 304 2.331100 5640 200 1 305 5.5 381 2750 200 1 308 1.67 236 2420 200 1 310 5.5263 2210 200 1 312 4.67 615 3250 200 1 314 5 153 961 200 1 316 2.33 5953550 200 1 318 5 407 1820 200 3 301 6 360 NC 200 3 304 4 517 NC 200 3305 1 350 NC 200 3 308 2.33 422 NC 200 3 310 5 303 NC 200 3 312 5 353 NC200 3 314 5 243 NC 200 3 316 4 952 NC 200 3 318 5 658 NC 200 7 301 3.67256 2050 200 7 304 1.67 1040 4420 200 7 305 2 298 2810 200 7 308 4.67399 4880 200 7 310 6 294 3250 200 7 312 5 616 3580 200 7 314 2 170 2050200 7 316 2.67 578 4250 200 7 318 4.33 579 2930 400 1 302 3 1230 7380400 1 303 5 466 3460 400 1 306 2.33 835 5810 400 1 307 5 874 6500 400 1309 5.5 1050 4450 400 1 311 4.33 1420 6250 400 1 313 3.33 1140 4810 4001 315 5 1280 4660 400 1 317 5 1280 7610 400 1 319 3.67 1040 6380 400 3302 2 1510 NC 400 3 303 1.67 667 NC 400 3 306 4 1700 NC 400 3 307 5 854NC 400 3 309 3 1000 NC 400 3 311 4 1660 NC 400 3 313 5 579 NC 400 3 3153 1410 NC 400 3 317 3 985 NC 400 3 319 2.33 1370 NC 400 7 302 0.5 4545310 400 7 303 3.33 781 5830 400 7 306 NC NC NC 400 7 307 4.67 657 9350400 7 309 5.5 509 4210 400 7 311 4.33 916 6980 400 7 313 4.67 447 5360400 7 315 3.33 1800 7430 400 7 317 3 1660 9780 400 7 319 4.33 1340 8880NC = not calculated

TABLE 40A D2 Receptor Occupancy (RO) % by Subject in Example 7B 200 mgTotal Daily Dose 400 mg Total Daily Dose MR IR MR IR (Lot 3Z) (Lot 1Z)(Lot 3Z) (Lot 1Z) Day D2 RO D2 RO D2 RO D2 RO Measured* Subject (%)Subject (%) Subject (%) Subject (%) 2 320 28 301 26 322 30 302 NC 2 32125 304 35 323 23 303 33 2 328 16 305 30 324 17 306 40 2 329 22 308 29325 33 307 51 2 332 20 310 22 330 29 309 39 2 333 21 312 27 331 42 31143 2 336 13 314 29 334 25 313 30 2 337 20 316 27 335 23 315 36 2 318 16317 33 2 319 34 Average 21 ± 4 27 ± 5 28 ± 7 38 ± 6 8 320 32 301 27 32230 302 34 8 321 39 304 NC 323 32 303 NC 8 328 33 305 28 324 35 307 49 8329 21 308 37 325 44 309 32 8 332 38 310 34 330 26 311 32 8 333 24 31231 331 36 313 40 8 336 20 314 35 334 50 315 36 8 337 32 316 34 335 37317 24 8 318 19 319 38 Average 30 ± 7 31 ± 5 36 ± 7 36 ± 7 NC = notcalculated *Measurements on Day 2 were conducted within 27 ± 1 hours ofadministration of the first dose, and measurements on Day 8 wereconducted within 27 ± 1 hours of administration of the seventh dose.

TABLE 40B Example 7B D2 RO % (MR-IR) and ±90% Confidence Interval (CI)of data plotted in FIG. 25 Total Daily Dose % RO % 90% CI 90% CI (mg)Day (MR AR) Lower Upper 200 1 −6.15 −10.5 −1.85 200 7 −0.75 −6.60 5.10400 1 −9.92 −15.9 −3.94 400 7 0.63 −5.95 7.20

TABLE 40C Data Plotted in FIG. 28A White Circles White Diamonds PlasmaTime (hr) D2 RO (%) Time (hr) Concentration (ng/mL) 27.27 33.5 0.16755.4 50.7 24.4 0.333 334 76.65 13.9 0.5 346 0.667 316 1 294 1.5 677 2432 2.5 668 3 516 3.5 389 4 272 6 163 8 96.8 10 69.9 12 55.6 24 21.2 369.84 48 7.02 72 1.48

It was surprisingly discovered, that embodiments of the modified releasepharmaceutical formulations of the present inventions can providesubstantially the same efficacy as comparable immediate releaseformulations at both lower blood plasma maximum concentrations (Cmax)and total blood plasma concentration (AUC), and with reduced adverseevents and/or side effects.

Referring to FIGS. 22C, 22H, 22J, 26A, 26B, 27A and 27B it can be seenthat the modified release formulations used in this study provide both alower Cmax a AUC relative to the comparator immediate releaseformulation. While FIGS. 24A-D show that the modified releaseformulation provided substantially similar D2 receptor occupancy of thatof a comparable immediate release formulation. It was discovered in thisstudy that brain D2 receptor occupancy (RO) correlated more with anexposure sustained above a threshold (e.g., 100 ng/mL) than with Cmax orAUC itself. The comparison of pharmacokinetic (PK) parameters betweenimmediate release (IR) and modified release (MR) formulations indicatedthat Cmax and total AUC were insufficient to explain the observed D2receptor occupancy.

In addition, the modified release formulations of the present inventionsshow reduced side effects (e.g. QT prolongation) compared to comparableimmediate release formulations. The modified release formulationsresulted in substantially lower QTc prolongation than the same dose ofthe IR formulation. FIG. 23 illustrates the improved safety (reduced QTprolongation) provided by the modified release formulation in thisstudy.

Mean estimates of the QTc prolongation for the 200 mg IR formulationstested in these studies were consistently above 10 ms threshold (13 and14 ms at geometric mean Cmax values of 490 and 580 ng/mL in subjects inExamples 7A Parts 1 and 2, respectively) and were successfully reducedto 5 and 8 ms (at geometric means of 240 and 370 ng/mL, respectively)for the 200 mg modified release formulations.

These studies demonstrated that embodiments of the modified releaseformulations of the present inventions similar to Lot 3Z, provided as200 mg or 400 mg daily doses of the API, provided markedly lower Cmax(for a 200 mg total daily dose the modified release formulation (MR)population geometric mean Cmax was 314 ng/mL and for a 400 mg daily doseof MR population geometric mean Cmax was 484 ng/mL vs. a populationgeometric mean Cmax of 599 ng/mL for a 200 mg total daily dose of the IRformulation), and achieved clinically meaningful reduction in QTprolongation relative to a comparable IR form, while maintainingsubstantially similar brain occupancy (D2 recpetors) at steady state ascompared to the same dose given in comparable IR form. The modifiedrelease formulations thus provided an improved therapeutic index forbrain occupancy versus QTc prolongation relative to comparable immediaterelease formulations.

Referring more specifically to the figures, FIGS. 24A and 24B comparebrain D2 receptor occupancies percentages for subjects 27±1 hour afterreceiving a first (1^(st)) total daily dose of either 200 mg or 400 mgof API as: an immediate release (IR) formulation (as tablets with aformulation substantially similar to Lot 1Z), in FIG. 24A; and amodified release (MR) formulation (as tablets with a formulationsubstantially similar to Lot 3Z) in FIG. 24B.

FIGS. 24C and 24D compare brain D2 receptor occupancies percentages forsubjects 27±1 hour after receiving a seventh (7^(th)) total daily doseof either 200 mg or 400 mg of API as: an immediate release (IR)formulation (as tablets with a formulation substantially similar to Lot1Z), in FIG. 24C; and a modified release (MR) formulation (as tabletswith a formulation substantially similar to Lot 3Z) in FIG. 24D.

The data plotted in FIGS. 24A, 24B, 24C and 24 D is presented in Table40A. The circles in FIGS. 24A, 24B, 24C and 24 D represent data forindividual subjects which have been displaced for clarity, thehorizontal bars represent the average for the respective group of datapoints, and vertical error bars are the ±1 standard deviations for theassociated average, also presented in Table 40A.

It was discovered in this study that brain D2 receptor occupancy issubstantially similar between the immediate release (IR) and modifiedrelease (MR) formulations despite the difference in maximum blood plasmaconcentrations (Cmax) and total blood plasma concentration over time(represented by AUC) between these formulations. This can be morereadily seen through a comparison of FIG. 25, FIG. 26A, FIG. 26B, FIG.27A and FIG. 27B. FIG. 25 plots the difference between the averageobserved D2 RO for subjects administered the MR formulation and thatobserved for subjects administered the IR formulation in this study,measured 27±1 hour after receiving the first daily dose and the seventhdaily does (where blood plasma concentration has reached a steadystate). FIG. 25 illustrates that the D2 RO percentage is substantiallysimilar between the immediate release and modified release formulationsof this study. FIGS. 26A and 26B present modified release formulationCmax normalized by the Cmax for an immediate release formulationadministered at the same total daily dose as the MR formulation, andpresented as a percentage where a value of 100 indicates Cmax IR equalsCmax MR.

FIG. 26A includes date presented in Examples 7A Parts 1 and 2, as wellas Example 7B, while FIG. 26B presents data for Example 7B at severaltime points during the course of the study (i.e. Day 1, Day 3, and Day7). FIG. 27A includes date presented in Examples 7A Parts 1 and 2, aswell as Example 7B, while FIG. 27B presents data for Example 7B atseveral time points during the course of the study (i.e. Day 1 and Day7).

FIGS. 26A and 26B show that the Cmax of the MR formulations isconsistently less than that of the IR formulations and FIGS. 27A and 27Bshow that the AUC of the MR formulations is consistently less than thatof the IR formulations, while FIG. 25 shows that the D2 RO % issubstantially the same between the IR and MR formulations of this study.Thus, the present MR formulations present an increased therapeutic indexrelative to the IR formulations, and the data of these studies indicatethat the MR formulations of this study (for example a formulationcomprising about 25% of an extended release agent) can providesubstantially similar therapeutic effect at reduced blood plasmaconcentrations (and thus with potentially less undesirable side effects)than a comparable IR formulation.

In addition, it was discovered that embodiments of the modified releaseformulations of the present inventions show a marked pharmacokinetic(PK) and pharmacodynamics (PD) disconnect in amisulpride brain occupancyrelative to amisulpride blood plasma concentration, that cannot beaccounted for or predicted with traditional models. It was discovered inthese studies (Examples 7A Parts 1 & 2 and Example 7B) that amisulprideexhibits: (1) time-hysteresis: the clearance from plasma is rapidcompared to the washout of brain occupancy, (2) dose-response: occupancyincreases with dose and receptor binding is not saturated, and (3)lack-of-accumulation: brain occupancy does not accumulate substantiallyto steady state.

The comparison of PK parameters between IR and MR (modified release)formulations indicated that Cmax and total AUC were insufficient toexplain the observed brain occupancies under traditional models. Forexample, conventional linear direct effect (fails to account forobserved hysteresis), Emax direct effect (fails to account for observedhysteresis and dose response), receptor binding with effect-compartment(fails to account for observed lack of accumulation),concentration-difference (fails to account for observed hysteresis), andratio (fails to account for observed lack of accumulation) models.

The observed time-hysteresis (the clearance from plasma is rapidcompared to the washout of brain occupancy) can be discerned, forexample, in the data of FIGS. 22C, 22H, 22J and Tables 26A-C (showingamisulpride blood plasma concentration over time) to the observed D2receptor occupancy (see, for example FIGS. 24A-B and FIG. 28A) it wassurprisingly discovered that single oral doses resulted in brainoccupancies that far outlasted (approximately a 5-day washout for D2receptor occupancy) the plasma PK (approximately 24-hour washoutobserved for blood plasma concertation). Referring to FIG. 28A, thisobserved behavior is illustrated for a single subject in these studies,where the amisulpride blood plasma concertation as a function of time(white circles) is compared to D2 receptor occupancy (white diamonds) asa function of time. Hysteresis was observed in all subjects where D2receptor occupancy was measured, and this long duration of brainoccupancy was unexpected.

The observed D2 receptor occupancy and pharmacokinetics for the modifiedrelease formulation support the conclusion that lasting effects due tothese distribution kinetics would also be present at serotonin 5-HT7receptors for the modified release formulations of the presentinventions, and thus supports the conclusion that the therapeutic effectassociated with 5-HT7 receptor occupancy will be substantially similarbetween the modified release formulations of the present invention andcomparable IR formulations.

The observed dose-response (occupancy increases with dose and receptorbinding is not saturated), can be discerned, for example, in the data ofFIGS. 24A-D and 25.

The observed lack-of-accumulation (brain occupancy does not accumulatesubstantially to steady state) can be discerned, for example, incomparing FIGS. 24A and 24B to FIGS. 24C and 24D, and is furtherillustrated in FIG. 28B. FIG. 28B compares observed D2 receptoroccupancy as measured in Example 7B (white circles where total dailydose is indicated) to predicted accumulation (solid lines, dosage forprediction is indicated); where the prediction was made using atraditional receptor-binding model using single dose data from thestudies of Example 7A. In marked contrast to the predictions by thetraditional receptor-binding model, brain occupancy did not accumulateover 7 daily doses.

Without being held to theory, the inventors have developed a noveldistribution model having an additional transit step in the effect(brain) compartment, that accurately matches the measured data andrecapitulated the three key observations above: time-hysteresis,dose-response, and lack-of-accumulation. Both simulations and analyticalsolutions employing the novel distribution model describe how thereduced blood plasma exposures with modified release (MR) formulationscan still attain brain D2 receptor occupancies equivalent to thoseobserved for the immediate release (IR) formulations. In this novelmodel, transient increases in plasma concentration do not appreciablychange brain occupancy when they occur over shorter time durations,consistent with the experimental observations in these studies.

TABLE 41A Cmax and ±90% Confidence Interval (CI) of data plotted in FIG.26A Total Daily % Cmax 90% CI 90% CI Subjects Dose (mg) (MR/IR) LowerUpper Parts 1 & 2 Example 7A 200 53.2 46.4 61.0 Parts 1 Example 7A 20045.1 37.2 54.7 Parts 2 Example 7A 200 63.4 52.8 76.1 Example 7B 200 56.143.9 71.7 Example 7B 400 49.2 38.3 63.1

TABLE 41B Example 7B Cmax and ±90% Confidence Interval (CI) of dataplotted in FIG. 26B Total Daily % Cmax 90% CI 90% CI Dose (mg) Day(MR/IR) Lower Upper 200 1 49.1 29.6 81.6 200 3 52.5 34.7 79.5 200 7 68.545.9 102 400 1 36.6 22.3 60.1 400 3 44.3 32.2 61.1 400 7 74.5 44.9 124

TABLE 41C Normalized AUC and ±90% Confidence Interval (CI) of dataplotted in FIG. 27A Total Daily % AUC 90% CI 90% CI Subjects Dose (mg)(MR/IR) Lower Upper Parts 1 & 2 Example 7A 200 70.0 64.9 75.5 Parts 1Example 7A 200 69.3 61.3 78.3 Parts 2 Example 7A 200 70.8 64.2 78.1Example 7B 200 61.5 48.3 78.3 Example 7B 400 61.5 47.1 80.2

TABLE 41D Normalized AUC and ±90% Confidence Interval (CI) of dataplotted in FIG. 27B Total Daily % AUC 90% CI 90% CI Dose (mg) Day(MR/IR) Lower Upper 200 1 52.0 36.8 73.4 200 7 72.8 57.7 92 400 1 47.834.4 66.3 400 7 78.3 55.2 111

Crystal Forms of Enantiomeric Amisulpride

In various embodiments, are provided a distinct polymorph of(R)-(+)-amisulpride, (S)-(−)-amisulpride, or both, is used in variousembodiments of the compositions, formulations, methods and medicaments.

Polymorphism is the ability of an element or compound to crystallizeinto distinct crystalline phases. Although the term polymorph impliesmore than one morphology, the term is still used in the art, and herein,to refer to a crystalline structure of a compound as a polymorph evenwhen only one crystalline phase is currently known. Thus, polymorphs aredistinct solids sharing the same molecular formula as other polymorphsand the amorphous (non-crystalline) phase, however since the propertiesof any solid depends on its structure, polymorphs often exhibit physicalproperties distinct from each other and the amorphous phase, such asdifferent solubility profiles, different melting points, differentdissolution profiles, different thermal stability, differentphotostability, different hygroscopic properties, different shelf life,different suspension properties and different physiological absorptionrates. Inclusion of a solvent in the crystalline solid leads tosolvates, and in the case of water as a solvent, hydrates, often leadsto a distinct crystalline form with one or more physical properties thatare distinctly different from the non-solvated and non-hydrated (e.g.,free base) crystalline form. In various embodiments, Form A and A′ areanhydrous, e.g., substantially free of water and solvent.

As used herein, the term “polymorph” refers to different crystalstructures achieved by a particular chemical entity. As used herein, theterm “solvate” refers to a crystal form where a stoichiometric ornon-stoichiometric amount of solvent, or mixture of solvents, isincorporated into the crystal structure. Similarly, the term “hydrate”refers to a crystal form where a stoichiometric or non-stoichiometricamount of water is incorporated into the crystal structure.

In various embodiments, (R)-amisulpride and (S)-amisulpride areindependently provided in a free base crystal form, and thus without anywater or solvent incorporated into the crystal structure. It has beenfound that (R)-amisulpride and (S)-amisulpride can exist in at least onesuch free base crystal form, or polymorph, which is referred to hereinas Form A for crystalline (R)-amisulpride, and Form A′ for crystalline(S)-amisulpride.

Form A and Form A′ are also described U.S. patent application Ser. No.16/209,263 filed on Dec. 4, 2018, and is hereby incorporated herein byreference in its entirety.

Crystal forms of amisulpride, enantiomeric amisulpride, and crystallineforms of their salts, hydrates and solvates may be characterized anddifferentiated using a number of conventional analytical techniques,including but not limited to X-ray powder diffraction (XRPD) patterns,nuclear magnetic resonance (NMR) spectra, Raman spectra, Infrared (IR)absorption spectra, dynamic vapor sorption (DVS), Differential Scanningcalorimetry (DSC), and melting point. Chemical purity may becharacterized using a number of conventional analytical techniques,including but not limited to high performance liquid chromatography(HPLC) and gas chromatography (GC). For example, one skilled in the artcould use a reverse phase gradient HPLC method or a reverse phaseisocratic HPLC method to determine organic impurities, a headspace GCmethod to determine residual solvents, coulometric titration (KarlFischer) to determine water content, and a reverse phase isocratic HPLCmethod or a polar organic phase isocratic HPLC method to determine theamount of drug product in a sample. Chiral purity (also known asenantiomeric purity) may be characterized using a number of conventionalanalytical techniques, including but not limited to chiral highperformance liquid chromatography (HPLC).

In various embodiments, the crystal forms of racemic amisulpride,enantiomeric amisulpride, and enantiomeric amisulpride solvates arecharacterized by X-ray powder diffraction (XRPD). XRPD is a technique ofcharacterizing a powdered sample of a material by measuring thediffraction of X-rays by the material. The result of an XRPD experimentis a diffraction pattern. Each crystalline solid produces a distinctivediffraction pattern containing sharp peaks as a function of thescattering angle 2θ (2-theta). Both the positions (corresponding tolattice spacing) and the relative intensity of the peaks in adiffraction pattern are indicative of a particular phase and material.This provides a “fingerprint” for comparison to other materials. Incontrast to a crystalline pattern comprising a series of sharp peaks,amorphous materials (liquids, glasses etc.) produce a broad backgroundsignal in a diffraction pattern.

It is to be understood that the apparatus employed, humidity,temperature, orientation of the powder crystals, and other parametersinvolved in obtaining an XRPD pattern may cause some variability in theappearance, intensities, and positions of the lines in the diffractionpattern. An XRPD pattern that is “substantially in accord with” that ofa Figure (FIG.) provided herein (e.g., FIG. 11B) is an XRPD pattern thatwould be considered by one skilled in the art to represent a compoundpossessing the same crystal form as the compound that provided the XRPDpattern of that Figure. That is, the XRPD pattern may be identical tothat of the Figure, or more likely it may be somewhat different. Such anXRPD pattern may not necessarily show each of the lines of thediffraction patterns presented herein, and/or may show a slight changein appearance, intensity, or a shift in position of said lines resultingfrom differences in the conditions involved in obtaining the data. Aperson skilled in the art is capable of determining if a sample of acrystalline compound has the same form as, or a different form from, aform disclosed herein by comparison of their XRPD patterns.

For example, one skilled in the art could use a chiral HPLC method (e.g.polar organic mode isocratic HPLC) to determine the enantiomericidentity of an amisulpride sample and if, for example, the sample isidentified as (R)-amisulpride, one skilled in the art can overlay anXRPD pattern of the amisulpride sample with FIG. 11B and/or FIG. 12B,and using expertise and knowledge in the art, readily determine whetherthe XRPD pattern of the sample is substantially in accordance with theXRPD pattern of crystalline (R)-amisulpride of Form A presented in FIG.11B. If, for example, HPLC identifies the sample as being(R)-amisulpride and the sample XRPD pattern is substantially in accordwith FIG. 11B, the sample can be readily and accurately identified as(R)-amisulpride of Form A.

In various embodiments, the crystal forms of racemic amisulpride,enantiomeric amisulpride, and enantiomeric amisulpride solvates arecharacterized by melting point. Melting points were determined byconventional methods such as capillary tube and may exhibit a range overwhich complete melting occurs, or in the case of a single number, a meltpoint of that temperature ±1° C.

In various embodiments, the crystal forms of racemic amisulpride,enantiomeric amisulpride, and enantiomeric amisulpride solvates arecharacterized by differential scanning calorimetry (DSC). DSC is athermoanalytical technique in which the difference in the amount of heatrequired to increase the temperature of a sample and a reference ismeasured as a function of temperature. Both the sample and reference aremaintained at substantially the same temperature throughout theexperiment. The result of a DSC experiment is a curve of heat flowversus temperature, called a DSC thermogram.

In various embodiments, the hygroscopicity of crystal forms of racemicamisulpride, enantiomeric amisulpride, and enantiomeric amisulpridesolvates are characterized by dynamic vapor sorption (DVS). DVS is agravimetric technique that measures how much of a solvent is absorbed bya sample by varying the vapor concentration surrounding the sample(e.g., relative humidity) and measuring the change in mass. In thepresent application, DVS is used to generate water sorption isotherms,which represent the equilibrium amount of vapor sorbed as a function ofsteady state relative vapor pressure at a constant temperature.

As used herein, the term “substantially non-hygroscopic” refers to acompound exhibiting less than a 1% maximum mass change in water sorptionisotherms, at 25° C. scanned over 0 to 95% relative humidity, asmeasured by dynamic vapor sorption (DVS).

In various embodiments, the compositions use new crystalline forms ofenantiomeric amisulpride, Form A and Form A′. Forms A and A′ have beenfound to be a distinct polymorph, different from the crystalline form ofa racemic amisulpride, having a distinctly different structure and XRPDpattern, as well as physical properties. Table 42 compares variousproperties and data on Form A crystals of (R)-amisulpride and Form A′crystals of (S)-amisulpride where the Figure (FIG.) references are tofigures in the present application. The Specific Rotation data wasobtained by polarimetry, the compound was dissolved in methanol atnominal concentration of c=1 using the 589 nm (Sodium Line). It is to beunderstood that upon dissolution of the compound it is no longer of acrystalline form, thus one of ordinary skill in the art will understandthat the specific rotation in Table 42 refers to that of thenon-crystalline compound.

TABLE 42 Physical Properties of Forms A and A′ (R)-amisulpride(S)-amisulpride Form A Form A′ # of Solid Phases    1    1 MeltingPoint, ⁰C  102  102 DSC Thermograph FIG. 11A FIG. 12A XRPD Pattern FIG.11B FIG. 12B Micrograph Image FIG. 11C FIG. 12C Specific Rotation [α]²⁰_(D) = −5.0 · 10¹ [α]²⁰ _(D) = −5.0 · 10¹ (MeOH, c = 1) (MeOH, c = 1)Solubility (mg/mL): Water    2    2 (solution pH) (10.2) (10.3) 0.05MAcetate Buffer >100 >100 (solution pH) (4.5) (4.5) Ethyl Acetate     3.9      3.9 Acetone/MtBE 1:4    8    8 Acetone/MtBE 1:9    2    2Simulated Gastric Fluid >100 >100 (no enzyme) (pH adjusted to 1.1) (pHadjusted to 1.2) Simulated Intestinal Fluid >100 >100 (no enzyme) (pHadjusted to 6.7) (pH adjusted to 6.9)

In various embodiments, Form A is a crystalline form of (R)-amisulpridecharacterized by an XRPD pattern comprising peaks, in terms of 2-theta,at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°. In various embodiments, thecrystalline form of (R)-amisulpride is characterized by three or morepeaks in its XRPD pattern selected from those at 7.0±0.2°, 9.7±0.2°,15.4±0.2°, 19.4±0.2°, 20.1±0.2°, 21.0±0.2°, 23.2±0.2°, and 29.3±0.2°, interms of 2-theta. In various embodiments, Form A of (R)-amisulpride ischaracterized by an XRPD pattern substantially in accord with FIG. 11B.

In various embodiments, the crystalline Form A of (R)-amisulpride ischaracterized by the following properties, an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 15.4±0.2°, amelting point of 102±3° C., a chiral purity of greater than about 99%, achemical purity greater than about 99%, a residual solvent content ofless than about 1000 ppm, and is substantially non-hygroscopic.

In various embodiments, the crystalline Form A of (R)-amisulpride ischaracterized by the following properties, an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 15.4±0.2° and oneor more of the following:

-   -   (a) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 19.4±0.2° and 29.3±0.2°;    -   (b) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 20.1±0.2°, 21.0±0.2°, and        23.2±0.2°;    -   (c) a melting point of 102±3° C.;    -   (d) a differential scanning calorimetry thermogram comprising a        peak at 101±3° C.;    -   (e) a differential scanning calorimetry thermogram substantially        in accord with FIG. 11A;    -   (f) a chiral purity of greater than about: (i) 90%, (ii)        95%, (iii) 97%, (iv) 99%, (v) 99.5%, (vi) 99.7%, or (vii) 99.9%;    -   (g) a chemical purity of greater than about: (i) 80%, (ii)        90%, (iii) 95%, (iv) 97%, (v) 99%, (vi) 99.5%, (vii) 99.7%,        or (viii) 99.9%;    -   (h) residual solvents present in an amount less than about: (i)        8000 ppm, (ii) 6000 ppm, (iii) 4000 ppm, (iv) 2000 ppm, (v) 1000        ppm, (vi) 800 ppm, or 500 ppm; and    -   (i) as measured by dynamic vapor sorption (DVS), at 25° C.        scanned over 0 to 95% relative humidity, a maximum mass change        in water sorption isotherms of less than about (i) 2%, (ii)        1%, (iii) 0.5%, or (iv) 0.4%.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°. In various embodiments, thecrystalline form of (S)-amisulpride is Form A′ characterized by three ormore peaks in its XRPD pattern selected from those at 7.0±0.2°,9.7±0.2°, 15.4±0.2°, 19.4±0.2°, 20.1±0.2°, 21.0±0.2°, 23.2±0.2°, and29.3±0.2°, in terms of 2-theta. In various embodiments, Form A′ of(S)-amisulpride is characterized by an XRPD pattern substantially inaccord with FIG. 12B.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by the following properties, an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 15.4±0.2°, amelting point of 102±3° C., a chiral purity of greater than about 99%, achemical purity greater than about 99%, a residual solvent content ofless than about 1000 ppm, and is substantially non-hygroscopic.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by the following properties, an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 15.4±0.2° and twoor more of the following:

-   -   (a) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 19.4±0.2° and 29.3±0.2°;    -   (b) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 20.1±0.2°, 21.0±0.2°, and        23.2±0.2°;    -   (c) a melting point of 102±3° C.;    -   (d) a differential scanning calorimetry thermogram comprising a        peak at 101±3° C.;    -   (e) a differential scanning calorimetry thermogram substantially        in accord with FIG. 12A;    -   (f) a chiral purity of greater than about: (i) 90%, (ii)        95%, (iii) 97%, (iv) 99%, (v) 99.5%, (vi) 99.7%, or (vii) 99.9%;    -   (g) a chemical purity of greater than about: (i) 80%, (ii)        90%, (iii) 95%, (iv) 97%, (v) 99%, (vi) 99.5%, (vii) 99.7%,        or (viii) 99.9%;    -   (h) residual solvents present in an amount less than about: (i)        8000 ppm, (ii) 6000 ppm, (iii) 4000 ppm, (iv) 2000 ppm, (v) 1000        ppm, (vi) 800 ppm, or 500 ppm; and    -   (i) as measured by dynamic vapor sorption (DVS), at 25° C.        scanned over 0 to 95% relative humidity, a maximum mass change        in water sorption isotherms of less than about (i) 2%, (ii)        1%, (iii) 0.5%, or (iv) 0.4%.

In various embodiments, crystalline enantiomeric amisulpride of Form Ais characterized at least in part by having an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2° and nothaving a peak, in terms of 2-theta, at 6.6±0.3° that has a heightgreater than about 5% of the highest of the peaks at 7.0±0.2°, 9.7±0.2°,and 19.4±0.2°.

In various embodiments, crystalline enantiomeric amisulpride of Form A′is characterized at least in part by having an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2° and nothaving a peak, in terms of 2-theta, at 6.6±0.3° that has a heightgreater than about 5% of the highest of the peaks at 7.0±0.2°, 9.7±0.2°,and 19.4±0.2°.

In various embodiments, XRPD information and patterns are used tocharacterize Forms A and A′. FIGS. 11B and 12B XRPD patterns for,respectively, (R)-amisulpride Form A and (S)-amisulpride Form A′. Tables43-46 present further information and details on XRPD patterns obtainedfor Forms A and A′.

The XRPD patterns of both (R)-amisulpride Form A (FIG. 11B) and(S)-amisulpride Form A′ (FIG. 12B) show prominent peaks, in terms of2-theta, at 7.0±0.2°, 9.7±0.2°, 15.4±0.2°, 19.4±0.2°, 20.1±0.2°,21.0±0.2°, 23.2±0.2°, and 29.3±0.2°.

In various embodiments, Form A of (R)-(+)-amisulpride characterized by apowder x-ray diffraction pattern comprising peaks, in terms of 2-theta,at 7.0±0.2°, 9.7±0.2°, and 15.4±0.2°. In some embodiment, Form A of(R)-(+)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at9.3±0.2°, and 19.4±0.2°. In some embodiment, Form A of(R)-(+)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at14.9±0.2°, 16.9±0.2°, and 20.1±0.2°. In some embodiment, Form A of(R)-(+)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at19.0±0.2°, 21.0±0.2°, and 23.2±0.2°.

In various embodiments, Form A′ of (S)-(−)-amisulpride characterized bya powder x-ray diffraction pattern comprising peaks, in terms of2-theta, at 7.0±0.2°, 9.7±0.2°, and 15.4±0.2°. In some embodiments, FormA′ of (S)-(−)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at9.3±0.2°, and 19.4±0.2°. In some embodiments, Form A′ of(S)-(−)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at14.9±0.2°, 16.9±0.2°, and 20.2±0.2°. In some embodiments, Form A′ of(S)-(−)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at19.1±0.2°, 21.0±0.2°, and 23.2±0.2°.

The DSC thermograms of FIGS. 11A and 12A were obtained using TAInstruments Q100 differential scanning calorimeter. Each sample washeated in a sealed pan under a 50 mL/min nitrogen purge at a heatingrate of 10° C./min, from a starting temperature of 25° C. up to a finaltemperature of 150° C. or 200° C.

The micrograph images of FIGS. 11C and 12C were obtained using the NikonMicrophot polarizing light microscope. Samples were prepared in IsoparG/3% Lecithin, and imaged using cross-polarized light with a quarterwave plate.

The XRPD patterns of FIGS. 11B and 12B were performed using a RigakuMiniFlex II Desktop X-Ray diffractometer using Cu radiation. The tubevoltage and amperage were set to 30 kV and 15 mA, respectively. Thescattering slit was fixed at 1.25° and the receiving slit was fixed at0.3 mm. Diffracted radiation was detected by a NaI scintillationdetector. A θ-2θ continuous scan at 1.0°/min with a step size of0.02-0.05° from 3 to 45° 2θ was used. Data were collected and analyzedusing Jade 8.5.4. Each sample was prepared for analysis by placing it ina low background, round, 0.1 mm indent sample holder. In FIGS. 11B and12B, 2-Theta angles in degrees (x-axis) are plotted against peakintensity in terms of the count rate per second (y-axis).

Crystals of (R)-Amisulpride Form A

For single crystal structure determination, a colorless needle havingapproximate dimensions of 0.25×0.04×0.02 mm³, was mounted on a polymerloop in random orientation. Preliminary examination and data collectionwere performed on a Rigaku SuperNova diffractometer, equipped with acopper anode microfocus sealed X-ray tube (Cu Kα λ=1.54184 Å) and aDectris Pilatus3 R 200K hybrid pixel array detector. Cell constants andan orientation matrix for data collection were obtained fromleast-squares refinement using the setting angles of 16528 reflectionsin the range 3.5080°<θ<77.2950°. The data was collected to a maximumdiffraction angle (2θ) of 155.296°, at a temperature of 100 K. A totalof 35826 reflections were collected, of which 12849 were unique. Lorentzand polarization corrections were applied to the data. The linearabsorption coefficient is 1.728 mm⁻¹ for Cu Kα radiation. An empiricalabsorption correction using CRYSALISPRO was applied (CrysAlisPro1.171.38.41r (Rigaku Oxford Diffraction, 2015). Transmissioncoefficients ranged from 0.659 to 1.000. Intensities of equivalentreflections were averaged. The agreement factor for the averaging was5.72% based on intensity.

A calculated XRPD pattern was generated for Cu radiation using MERCURYand the atomic coordinates, space group, and unit cell parameters fromthe single crystal structure (Macrae, C. F. et al., J. J. Appl. Cryst.,2006, 39, 453-457). It is to be understood that because the singlecrystal data are collected at low temperatures (100 K), peak shifts maybe evident between the pattern calculated from low temperature data androom temperature experimental powder diffraction patterns, particularlyat high diffraction angles. FIG. 29 shows the calculated XRPD pattern ofForm A.

In various embodiments, the crystal system of (R)-amisulpride Form Acrystals is triclinic and the space group is P1. Referring to FIG. 11C,by microscopy the solids consisted of birefringent spherulites of longneedles. Further details of the crystal data and crystallographic datacollection parameters are summarized in Table 43 and a listing of thepeaks of the experimental XRPD of FIG. 11B are listed in Table 44. Thecalculated XRPD pattern of Form A is shown in FIG. 29.

In some embodiment, the crystalline form of (R)-(+)-amisulpride ischaracterized by single crystal x-ray diffraction having a P1 spacegroup and cell formula units (Z) of 4. In some embodiments, crystallineform of (R)-(+)-amisulpride has unit cell parameters: a is about 12.3 Å,b is about 12.8 Å, c is about 14.1 Å, α is about 64.0°, β is about73.4°, and γ is about 75.9°.

TABLE 43 (R)-amisulpride Form A Single Crystal Data and Data CollectionParameters Empirical formula C₁₇H₂₇N₃O₄S Molecular weight (g mol⁻¹)  369.47 Temperature (K)   100 Wavelength (Å)     1.54184 Crystal systemtriclinic Space group P1 Unit cell parameters a = 12.3348(4) Å α =64.033(4)° b = 12.8343(6) Å β = 73.431(3)° c = 14.1403(6) Å γ =75.881(3)° Unit cell volume (Å³) 1910.47(15) Cell formula units, Z     4Calculated density (g cm⁻³)     1.285 Absorption coefficient (mm⁻¹)    1.728 F(000)   792 Crystal size (mm³) 0.25 × 0.04 × 0.02 Reflectionsused for cell 16528 measurement ϑ range for cell measurement  3.5080⁰-77.2950° Total reflections collected 35826 Index ranges −15 ≤ h ≤ 15;−16 ≤ k ≤ 16; −17 ≤ l ≤ 17 ϑ range for data collection ϑ_(min) = 3.552°,ϑ_(max) = 77.648° Completeness to θ_(max) 97.6% Completeness to θ_(full)= 67.684° 99.8% Absorption correction multi-scan Transmissioncoefficient range 0.659-1.000 Refinement method full matrixleast-squares on F² Independent reflections 12849 [R_(int) = 0.0572,R_(σ) = 0.0533] Reflections [/>2σ(/)] 11460Reflections/restraints/parameters 12849/3/954 Goodness-of-fit on F² S =1.02 Final residuals [I > 2σ(I)] R = 0.0607, R_(w) = 0.1675 Finalresiduals [all reflections] R = 0.0658, R_(w) = 0.1739 Largest diff.peak and hole (e Å⁻³) 0.640, −0.670 Max/mean shift/standard uncertainty0.000/0.000 Absolute structure determination Flack parameter: 0.009(18)Hooft parameter: 0.007(12) Friedel coverage: 60.2%

TABLE 44 (R)-amisulpride Form A XRPD (FIG. 11B) Peak List 2-ThetaRelative Height 7.00 75 7.42 1.6 9.34 26.9 9.72 68.3 9.95 1.5 11.00 6.711.66 1.2 12.72 2.3 13.26 11.3 13.90 5.2 14.41 4.8 14.72 13.5 14.90 3115.40 100 15.94 4 16.64 7.9 16.92 28 17.44 14.8 17.70 4 18.66 7.5 19.0429.3 19.42 87 20.12 63.7 20.98 34.8 21.62 3.5 21.88 7.8 22.32 3.8 22.612.5 23.22 89.3 24.34 8.1 24.80 8.7 25.26 3 25.56 17 25.78 4.3 26.20 3.226.68 15.8 27.10 11.3 28.12 3.5 28.28 2.6 28.82 5.2 29.26 42.2 29.56 5.929.76 3.7 30.32 1.9 30.92 1.7 31.02 2.6 31.70 4.3 31.94 3.8 32.26 2.232.84 8.9 33.22 2.7 34.16 2.7 34.55 2.2 34.97 1.7 35.24 1.1 35.48 0.935.76 2.9 37.00 1.9 37.44 1.3 38.58 3.2 38.88 3.4 39.50 1.6 39.76 2.140.38 2.5 40.80 3.7 41.39 1.4 41.68 1.5 42.68 3.7 43.28 2.8 43.52 4.7

Crystals of (S)-Amisulpride Form A′

For single crystal structure determination, a colorless needle havingapproximate dimensions of 0.20×0.04×0.02 mm³, was mounted on a polymerloop in random orientation. Preliminary examination and data collectionwere performed on a Rigaku SuperNova diffractometer, equipped with acopper anode microfocus sealed X-ray tube (Cu Kα λ=1.54184 Å) and aDectris Pilatus3 R 200K hybrid pixel array detector. Cell constants andan orientation matrix for data collection were obtained fromleast-squares refinement using the setting angles of 14943 reflectionsin the range 3.5170°<θ<77.9740°. The data was collected to a maximumdiffraction angle (2θ) of 156.71°, at a temperature of 100 K. A total of36278 reflections were collected, of which 12840 were unique. Lorentzand polarization corrections were applied to the data. The linearabsorption coefficient is 1.728 mm-1 for Cu Kα radiation. An empiricalabsorption correction using CRYSALISPRO was applied (CrysAlisPro1.171.38.41r (Rigaku Oxford Diffraction, 2015). Transmissioncoefficients ranged from 0.791 to 1.000. Intensities of equivalentreflections were averaged. The agreement factor for the averaging was5.83% based on intensity.

A calculated XRPD pattern was generated for Cu radiation using MERCURYand the atomic coordinates, space group, and unit cell parameters fromthe single crystal structure (Macrae, C. F. et al., J. J. Appl. Cryst.,2006, 39, 453-457). It is to be understood that because the singlecrystal data are collected at low temperatures (100 K), peak shifts maybe evident between the pattern calculated from low temperature data androom temperature experimental powder diffraction patterns, particularlyat high diffraction angles. FIG. 30 shows the calculated XRPD pattern ofForm A′.

In various embodiments, the crystal system of (S)-amisulpride Form A′crystals is triclinic and the space group is P1. Referring to FIG. 12C,by microscopy the solids consisted of birefringent spherulites of longneedles. Further details of the crystal data and crystallographic datacollection parameters are summarized in Table 45 and a listing of thepeaks of the experimental XRPD of FIG. 12B are listed in Table 46. Thecalculated XRPD pattern of Form A′ is shown in FIG. 30.

In some embodiments, the crystalline form of (S)-(−)-amisulpride ischaracterized by single crystal x-ray diffraction having a P1 spacegroup and cell formula units (Z) of 4. In some embodiments, thecrystalline form of (S)-(−)-amisulpride has unit cell parameters: α isabout 12.4 Å, b is about 12.8 Å, c is about 14.1 Å, α is about 64.2°, βis about 73.6°, and γ is about 75.8°.

TABLE 45 (S)-amisulpride Form A′ Single Crystal Data and Data CollectionParameters Empirical formula C₁₇H₂₇N₃O₄S Formula weight (g mol⁻¹)  369.47 Temperature (K)   100 Wavelength (A)     1.54184 Crystal systemtriclinic Space group P1 Unit cell parameters a = 12.3795(4) Å α =64.246(3)° b = 12.7526(4) Å β = 73.598(3)° c = 14.1438(4) Å γ =75.797(3)° Unit cell volume (Å³) 1909.71(11) Cell formula units, Z     4Calculated density (g cm⁻³)     1.285 Absorption coefficient (mm⁻¹)    1.728 F(000)   792 Crystal size (mm³) 0.2 × 0.04 × 0.02 Reflectionsused for cell 14943 measurement ϑ range for cell measurement3.5170°-77.9740° Total reflections collected 36278 Index ranges −15 ≤ h≤ 14; −16 ≤ k ≤ 16; −17 ≤ l ≤ 17 ϑ range for data collection ϑ_(min) =3.542°, ϑ_(max) = 78.355° Completeness to θ_(max) 97.6% Completeness toθ_(full) = 67.684° 99.9% Absorption correction multi-scan Transmissioncoefficient range 0.791-1.000 Refinement method full matrixleast-squares on F² Independent reflections 12840 [R_(int) = 0.0583,R_(σ) = 0.0539] Reflections [/>2σ(I)] 11066Reflections/restraints/parameters 12840/3/956 Goodness-of-fit on F² S =1.08 Final residuals [I>2σ(I)] R = 0.0613, R_(w) = 0.1732 Finalresiduals [all reflections] R = 0.0694, R_(w) = 0.1817 Largest diff.peak and hole (e Å⁻³) 0.470, −0.468 Max/mean shift/standard uncertainty0.000/0.000 Absolute structure determination Flack parameter: 0.008(18)Hooft parameter: 0.019(12) Friedel coverage: 58.8%

TABLE 46 (S)-amisulpride Form A′ XRPD (FIG. 12B) Peak List 2-ThetaRelative Height 7.02 100 9.34 28 9.74 62 11.05 5.6 13.28 15.2 13.94 7.814.92 20 15.42 66.2 16.90 23.9 17.44 8.9 18.68 7.4 19.08 34.2 19.44 74.420.16 70 21.00 41.2 21.9 12 22.36 3.1 23.20 72.1 24.34 5.7 24.87 7 25.6016.9 25.84 6.2 26.17 2.3 26.70 14.8 27.12 12.1 28.12 5.2 29.28 40.430.36 2.2 31.84 3.8 32.30 2.4 32.84 9 33.26 3.7 34.17 2.5 34.64 2 35.101.8 35.84 2.8 36.14 1.6 37.00 1.6 37.48 2.1 38.60 4.8 38.94 5.2 39.521.6 39.75 2.1 40.38 4.1 40.76 4.2 41.48 1.8 42.76 3.6 43.50 5.7 44.121.1

In various embodiments, the crystalline Form A of (R)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at two or more of 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, and a DSCthermogram having a peak at 101±3° C. In various preferred embodiments,the DSC thermogram has a single peak at 101±3° C.

In various embodiments, the a crystalline Form A of (R)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at two or more of 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, and a differentialscanning calorimetry thermogram substantially in accord with FIG. 11A.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at two or more of 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, and a DSCthermogram having a peak at 101±3° C. In various preferred embodiments,the DSC thermogram has a single peak at 101±3° C.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at two or more of 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, and a differentialscanning calorimetry thermogram substantially in accord with FIG. 12A.

In various embodiments, the crystalline Forms A and A′ of enantiomericamisulpride is substantially non-hygroscopic. In various embodiments,crystalline (R)-amisulpride of Form A has a maximum mass change of lessthan about 2%, less than about 1%, or less than about 0.5%, in watersorption isotherms as measured by dynamic vapor sorption (DVS), at 25°C. scanned over 0 to 95% relative humidity. In various embodiments,crystalline (S)-amisulpride of Form A′ has a maximum mass change of lessthan about 2%, less than about 1%, or less than about 0.5%, in watersorption isotherms as measured by dynamic vapor sorption (DVS), at 25°C. scanned over 0 to 95% relative humidity.

FIG. 12D shows a DVS water sorption isotherm for 19.077 mg of(S)-amisulpride crystal Form A′ and Table 47 lists the data plotted inFIG. 12D. As can be seen, crystalline (S)-amisulpride Form A′ issubstantially non-hygroscopic, exhibiting a maximum mass change of only0.35%.

TABLE 47 (S)-amisulpride Form A′ DVS Water Sorption Isotherm of FIG. 12DRelative Humidity % Change Mass (wt %) Time/step (min) 0 0.00 60.72 100.03 33.25 20 0.05 31.89 30 0.07 32.20 40 0.09 31.53 50 0.11 31.95 600.13 31.87 70 0.16 31.10 75 0.18 31.28 80 0.19 31.43 90 0.25 31.97 950.34 32.77 95 0.35 36.47 90 0.28 31.35 80 0.17 32.11 75 0.16 31.01 700.14 31.50 60 0.11 32.10 50 0.08 32.12 40 0.07 31.41 30 0.05 62.67 200.03 32.05 10 0.01 31.00 1 −0.01 32.02

In various aspects, provided are methods of making enantiomericamisulpride crystalline polymorphs of Form A and Form A′. Variousembodiments of the methods described below produce novel crystal formsand various embodiments of these methods are in themselves novel.

As used in the context of the methods of the present inventions, theterm “Form A” or “Form A′” refers to a method that produces acrystalline form of enantiomeric amisulpride having a powder x-raycrystal pattern comprising peaks, in terms of 2-theta, at least at7.0±0.2°, 9.7±0.2°, and one or more peaks at 15.4±0.2° and/or 19.4±0.2°;and preferably with additional peaks, in terms of 2-theta, at two ormore of: 15.4±0.2°, 19.4±0.2°, 20.1±0.2°, 21.0±0.2°, 23.2±0.2°, and29.3±0.2°; and in various preferred embodiments an powder x-ray crystalpattern substantially in accord with FIG. 11B, in the case of(R)-amisulpride, and FIG. 12B in the case of (S)-amisulpride.

Producing high yields of a specific crystalline form, and thus highpurity of that crystalline form, is often limited by the formation ofamorphous products and other crystalline forms that may, for example, bekinetically favored. It has been discovered through experimentation thatmaking crystalline enantiomeric amisulpride is complicated by the factthat traditional methods result in non-crystalline (amorphous)enantiomeric amisulpride, including methods that produce crystallineracemic amisulpride.

It has been discovered that formation of certain enantiomericamisulpride solvates as intermediates followed by conversion to the freebase allows for isolation of a crystalline form of enantiomericamisulpride (having a powder x-ray crystal pattern comprising peaks, interms of 2-theta, at least at 7.0±0.2°, 9.7±0.2°, and one or more peaksat 15.4±0.2° and/or 19.4±0.2°) that is greater than 90% by weight,greater than 95% by weight, greater than 97% by weight, greater than 99%by weight; or greater than 99.5% by weight of the enantiomericamisulpride starting material.

In various embodiments, methods of making crystalline enantiomericamisulpride, characterized by an XRPD pattern comprising peaks, in termsof 2-theta, at least at 7.0±0.2°, 9.7±0.2°, and one or more peaks at15.4±0.2° and/or 19.4±0.2°, comprise: (a) providing either(R)-amisulpride or (S)-amisulpride as a starting material, where(R)-amisulpride is provided as the starting material when crystalline(R)-amisulpride is the desired product and (S)-amisulpride is providedas the starting material when crystalline (S)-amisulpride is the desiredproduct; (b) solvating the starting material with a first solvent wherethe first solvent is a carbonyl containing compound having 5 carbons orless; (c) freeing the solvated starting material from the first solventby adding a second solvent other than water to form a mixture with astarting material solubility of less than about 20 wt/wt %; and then (d)isolating the crystalline form of the starting material having a powderx-ray crystal pattern comprising peaks, in terms of 2-theta, at least at7.0±0.2°, 9.7±0.2°, and 19.4±0.2°.

In various embodiments, the methods start with the provision of either(R)-amisulpride or (S)-amisulpride to make, respectively, crystalline(R)-amisulpride or crystalline (S)-amisulpride. It is to be understoodthat there are many acceptable ways to separate the enantiomers ofamisulpride to provide an enantiomeric starting material for the methodsof the present inventions. Examples 8 and 10 provide an in situ methodfor making enantiomerically enriched amisulpride starting material.

It is to be understood that the enantiomeric amisulpride startingmaterials are not necessarily crystalline, and often are amorphous or amixture of amorphous and crystalline form. In addition to separation ofenantiomers from a racemic starting material, suitable enantiomericstarting materials for the methods of the present inventions can also bedirectly synthesized.

It is to be understood that the ultimate chiral purity of thecrystalline form of the starting material is limited by the chiralpurity of the starting material. However, in various embodiments, it hasbeen found that the methods produce the crystalline form of the startingmaterial that has a chiral purity that is no less than the chiral purityof the starting material. Thus, in various embodiments, the presentmethods of making crystalline enantiomeric amisulpride (characterized byan XRPD pattern comprising peaks, in terms of 2-theta, at least at7.0±0.2°, 9.7±0.2°, and one or more peaks at 15.4±0.2° and/or 19.4±0.2°)provide said crystalline enantiomeric amisulpride having one or more of:a greater than about 90% chiral purity where the starting material has agreater than about 90% chiral purity; a greater than about 95% chiralpurity where the starting material has a greater than about 95% chiralpurity; a greater than about 97% chiral purity where the startingmaterial has a greater than about 97% chiral purity; a greater thanabout 99% chiral purity where the starting material has a greater thanabout 99% chiral purity.

It has been unexpectedly found that by proper selection of the firstsolvent, an intermediate solvate can be formed that upon subsequentconversion to the free base can provide an amisulpride product wheregreater than 90% by weight, greater than 95% by weight, greater than 97%by weight, greater than 99% by weight; or greater than 99.5% by weightof amisulpride product is in the form of crystalline enantiomericamisulpride of starting material, characterized by an XRPD patterncomprising peaks, in terms of 2-theta, at least at 7.0±0.2°, 9.7±0.2°,and one or more peaks at 15.4±0.2° and/or 19.4±0.2°.

The first solvent is a carbonyl containing compound having 5 carbons orless. Preferably, the first solvent has a water content of less than 3%by weight, more preferably less than 1% by weight, and more preferablyless than 0.5% by weight. It has been found that excess water in thefirst solvent interferes with, and can even prohibit, propercrystallization. Examples of such larger carbonyl containing solventinclude cyclohexanone. In various embodiments, the first solvent is analdehyde, ketone or ester. In various embodiments, the first solvent isethyl acetate, propyl acetate, or methyl ethyl ketone; and in variouspreferred embodiments the first solvent is ethyl acetate.

In various embodiments, the step of solvating includes basifying; forexample, by addition of a basic aqueous solution. In variousembodiments, a basic solution sufficient to raise the pH to greater than9.5, preferably to about 10, and in various embodiments between about9.5 and about 11, is added. In various embodiments, aqueous solutions ofpotassium carbonate are employed. It is to be understood that a varietyof basic solutions can be used to basify including, but not limited to,potassium carbonate, sodium carbonate, sodium hydroxide, and the like.

In various embodiments, the solvating step comprises multipleseparations between any aqueous phase and organic phase of the solventsystem of the solvating step, as may result, for example, frombasifying; the desired products being preferentially partitioned intothe organic phase. In various embodiments, the aqueous/organic solventsystem is heated to 30-40° C. to facilitate separation.

In various embodiments, subsequent to basifying, the organic phase isconcentrated and a stoichiometric excess of the first solvent is addedone or more times to facilitate complete conversion to the solvate. Inaddition, in various embodiments, repeated concentration and addition ofthe first solvent facilitates producing a concentrated solvate solutionhaving less than about 1 wt % water, less than about 0.7 wt % water, orless than about 0.4 wt % water, as determined by Karl Fischer titration.

In various embodiments, the reaction mixture is seeded with the desiredcrystalline form, (for example, seeding with crystalline (S)-amisulprideof Form A′ where the desired product is crystalline (S)-amisulpride ofForm A′) prior to addition of the second solvent. In variousembodiments, the step of solvating includes formation of a slurry by,for example, seeding the reaction mixture the desired crystalline formand cooling the reaction mixture below about 40° C., in variousembodiments below about 30° C., and preferably below about 20° C.

Following formation of the enantiomeric starting material solvate,(i.e., (R)-amisulpride solvate with the first solvent or a(S)-amisulpride solvate with the first solvent) the solvate is freedfrom the enantiomeric starting material to form the free base of theenantiomeric starting material under conditions that allow for theisolation of crystalline enantiomeric amisulpride characterized by anXRPD pattern comprising peaks, in terms of 2-theta, at least at7.0±0.2°, 9.7±0.2°, and one or more peaks at 15.4±0.2° and/or 19.4±0.2°.In various embodiments, the reaction mixture is seeded with the desiredcrystalline form, (for example, seeding with crystalline (S)-amisulprideof Form A′ where the desired product is crystalline (S)-amisulpride ofForm A′) prior to addition of the second solvent. In variousembodiments, the step of freeing comprises cooling the reaction mixtureto below about 40° C.

As used herein, the term “solvating” refers to the combination of(R)-amisulpride or (S)-amisulpride with a solvent.

As used herein, the terms “isolating” and “freeing” refer to separatingthe desired product from the environment in which it was formed ordetected. For example, separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the desired product.

In various embodiments, a second solvent (other than water) is added toform a mixture with a starting material solubility of less than about 20wt/wt %; less than about 10 wt/wt %; or less than about 5 wt/wt %. Oneof skill in the art will understand that in various embodiments thesecond solvent can be considered an anti-solvent as it lowers thesolubility of the mixture with respect to the desired product. It is tobe understood that a variety of compounds can be used as a secondsolvent including, but not limited to, methyl t-butyl ether, toluene,heptane, isopropanol, and the like. In various embodiments the secondsolvent is methyl t-butyl ether (MtBE).

A variety of procedures can be used to isolate the desired enantiomericcrystalline form of the starting material. In various embodiments, thestep of isolating comprises one or more of: (a) adding an anti-solvent;(b) cooling the mixture to below about 30° C., and in variousembodiments between about 10° C. and about 20° C.; and (c) adding seedcrystal of the R-enantiomer or S-enantiomer. In various embodiments, thestep of isolating comprises adding an anti-solvent and/or cooling thereaction mixture. In various embodiments use is made of seed crystals ofthe crystalline formed desired, and seed crystals can be obtained by oneof skill in the art using the teachings provided herein.

For example, Example 12 teaches methods of producing crystalline(R)-amisulpride ethyl acetate solvate. The product of these examplesupon drying above about 30° C., desolvates and converts to crystals ofcrystalline (R)-amisulpride free base of Form A and amorphous.Similarly, for example, Example 14 teaches a method producingcrystalline (S)-amisulpride ethyl acetate solvate. The product of theseexamples upon drying above about 30° C., desolvates and converts tocrystals of crystalline (S)-amisulpride free base of Form A′ andamorphous. Although the fraction of the solvate that converts to Form Aor Form A′ in the above examples is low, it is sufficient for obtainingseed crystals.

In various embodiments, the step of isolating the crystalline formcomprises seeding the reaction mixture with the desired crystallineform, (for example, seeding with crystalline (S)-amisulpride of Form A′where the desired product is crystalline (S)-amisulpride of Form A′)prior to addition of the second solvent, and, in various embodiments, aslurry is then formed by cooling the reaction mixture below about 40°C., in various embodiments below about 30° C., and preferably belowabout 20° C.

In various embodiments, the step of isolating comprises filtering aslurry comprising the desired crystalline form of the enantiomericamisulpride free base, washing the solid residue with a solvent systemcomprising the second solvent and the first solvent, and drying theresidue. In various embodiments, the wt/wt ratio of the second solventto first solvent (second solvent:first solvent) is greater than about1:9, and in various embodiments between about 1:9 to about 4:1. Invarious embodiments where the second solvent is MtBE and the firstsolvent ethyl acetate, the MtBe:ethyl acetate ratio is preferably about3:1.

In various embodiments, the methods of the present inventions for makingcrystalline enantiomeric amisulpride, characterized by an XRPD patterncomprising peaks, in terms of 2-theta, at least at 7.0±0.2°, 9.7±0.2°,and one or more peaks at 15.4±0.2° and/or 19.4±0.2°, compriserecrystallization. In the Examples, example methods that do not show arecrystallization step are noted as forming a “crude freebase,” howeverit is to be understood that this nomenclature is used only fordistinguishing the examples.

Recrystallization can be performed by a variety of techniques. Invarious embodiments, a step of recrystallization comprises (a)dissolving the crystalline enantiomeric amisulpride material in asolvent/anti-solvent solution; (b) cooling the solution comprising thestarting material and the solvent/anti-solvent solution; and (c) addinga seed crystal of the R or S enantiomeric amisulpride material. Invarious embodiments the step of dissolving includes heating of thesolution, to a temperature greater than 40° C. and below about 70° C.,and preferably between about 50° C. and about 65° C., and preferablyabout 60° C.

A variety of solvent/anti-solvent systems can be used. For example, invarious embodiments the solvent is acetone and the anti-solvent ismethyl t-butyl ether. In various embodiments, the solvent is isopropanol(IPA) and the anti-solvent is heptane. As understood by those of skillin the art, care must be taken in selection of the solvent/anti-solventsystem. For example, the inventors have found that in the IPA/heptanesystem a second liquid phase can form before seeding if the heptane toIPA ratio is greater than 1:1, that if a large excess of IPA is addedthe seeds will dissolve then crystallize upon addition of heptaneantisolvent and cooling, and that a preferred IPA:heptane:product ratiois 36:32:32.

Non-limiting examples of various embodiments of making crystallineenantiomeric amisulpride of Forms A and A′, or characterized by an XRPDpattern comprising peaks, in terms of 2-theta, at least at 7.0±0.2°,9.7±0.2°, and one or more peaks at 15.4±0.2° and/or 19.4±0.2°, arefurther illustrated and described in Examples 8, 9, 10 and 11.

Aspects, embodiments, and features of the preparation andcharacterization of crystal forms of enantiomeric amisulpride may befurther understood from the following examples, which should not beconstrued as limiting the scope of the present inventions.

Crystal Forms of Enantiomeric Amisulpride Examples

It is to be understood that the enantiomeric amisulpride startingmaterials are not necessarily crystalline, and often are amorphous or amixture of amorphous and crystalline form. In addition to separation ofenantiomers from a racemic starting material, suitable enantiomericstarting materials can also be directly synthesized.

Example 8: Synthesis ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(Crude Freebase)

150 g of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and 2000 g ofacetone were placed in a flask. The solution was cooled to −9° C., and74.3 mL of ethyl chloroformate was added to the flask. Then 88.9 mL of4-methyl morpholine was added over 1 hour. 81.4 g of(R)-(1-ethylpyrrolidin-2-yl)methanamine was added and the mixturestirred for 16 h. The reaction was then concentrated and 800 g of waterand 300 g of ethyl acetate were added. The mixture was agitated and theorganic layer removed, which contained theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidestarting material. The solution containing the starting material wasbasified by the addition of aqueous 20 wt % potassium carbonate and 2.5L of ethyl acetate was added. The aqueous layer was removed. The organiclayer was washed twice with water and concentrated to dryness. Then 800g of ethyl acetate was added and the mixture was concentrated. This wasrepeated once. The resulting oil was dissolved into 800 g of ethylacetate and concentrated to 600 mL. The solution was stirred at 30° C.and a slurry formed. The resulting slurry was cooled to 20° C. andagitated. 600 g of methyl t-butyl ether was added and the mixturestirred. The slurry was then filtered, washed with 3:1 wt/wt methylt-butyl ether:ethyl acetate and dried. 165 g ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidewas obtained as a crystalline solid.

Example 9: Recrystallization ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(Freebase Crystal Form A)

603.05 g ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(prepared substantially according to Example 8) and 500.3 g ofisopropanol were added to a flask with a stir bar and stopper. The flaskwas heated to 40° C. to form a solution. The solution was then polishfiltered and transferred to a reactor at 40° C. with agitator, nitrogenline, thermocouple and cooling water, using 122.81 g of isopropanol torinse the flask and polish filter. 603.2 g of heptane was added and thesolution was agitated. The reactor was cooled to a jacket temperature of35° C. and 6.91 g of isopropanol was added to the reactor drop wise tocreate a clear solution. The solution was agitated and then seeded with972 mg ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(Form A) and then agitated. The reactor was then cooled to 20° C. andthen agitated. 1889.24 g of heptane was added using an external pump.Following agitation, the slurry was filtered, washed with 15:85 wt/wtisopropanol:heptane and dried. 531.7 g ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof crystal Form A, having greater than 97% chiral purity, and greaterthan 99% chemical purity, was obtained, representing a yield of about88%.

An NMR spectrum of theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideobtained in Example 9 is illustrated in FIG. 13, having the followingcharacteristics: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 (t, J=7.24Hz, 3H) 1.26 (t, J=7.43 Hz, 3H) 1.56-1.76 (m, 3H) 1.84-1.94 (m, 1H)2.15-2.29 (m, 2H) 2.59-2.66 (m, 1H) 2.81-2.90 (m, 1H) 3.08-3.29 (m, 4H)3.70 (ddd, J=13.69, 7.24, 2.93 Hz, 1H) 3.94 (s, 3H) 5.53 (s, 2H) 6.22(s, 1H) 8.06 (br d, J=4.70 Hz, 1H) 8.53 (s, 1H).

Referring to FIGS. 11A-11C, FIGS. 11A-11C present data on theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,(R)-amisulpride, of crystal Form A obtained in Example 9. FIG. 11A is aDSC thermogram for crystal Form A of (R)-amisulpride obtained in Example9; FIG. 11B a XRPD pattern for crystal Form A of (R)-amisulprideobtained in Example 9; and FIG. 11C a micrograph image crystals ofcrystal Form A of the (R)-amisulpride obtained in Example 8.

Example 10: Synthesis ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(Crude Freebase)

153 g of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and 789 g ofacetone were placed in a flask fitted with a stir bar, a thermocoupleand a nitrogen line. The solution was cooled to −8° C., and then 70.4 gof ethyl chloroformate was added to the flask. An addition funnel wasfitted to the flask and 79.3 g of 4-methyl morpholine was added dropwise, maintaining the temperature below 0° C. The mixture was agitatedat −8° C. and then 55 g of (S)-(1-ethylpyrrolidin-2-yl)methanamine wasadded drop wise. The mixture was agitated at 0° C. for 1 hour, warmed toambient temperature and then further agitated at ambient temperature toprovideS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidestarting material. The reaction was then concentrated to minimum volumeand 822 g of water, followed by 311 g of ethyl acetate, was added. Themixture was agitated and the organic layer removed. The solution washeated to 35° ° C. and 755 g of ethyl acetate and 326 g of 40 wt %potassium carbonate (aq) were added. The mixture was agitated, thephases allowed to separate, and the aqueous layer removed. Then 296 g ofwater of water was added, the mixture agitated, the phases allowed toseparate and the aqueous layer removed. 302 g of water was added, themixture agitated, the phases allowed to separate and the aqueous layerremoved. The organic layer was transferred to a flask with a mechanicalstirrer, a thermocouple and a nitrogen line. The organic layer wasconcentrated to dryness and 531 g of ethyl acetate was added. Afteragitation, the solution was concentrated to 400 mL. Then 305 g of ethylacetate was added and the solution was concentrated to 400 mL and was0.35 wt % water by Karl Fischer titration. The solution was then cooledto 30° C. and seeded with 300 mg ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideand a slurry formed. The solution was then cooled to 20° C. andagitated, and 495 g of methyl t-butyl ether was added. The slurry wasthen filtered, washed with 3:1 wt/wt methyl t-butyl ether:ethyl acetateand dried. 160.7 g ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidewas obtained as a crystalline solid, representing a yield of about 74%.

Example 11: Recrystallization of:S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(Freebase Crystal Form A′)

300.19 g ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(prepared substantially according to Example 10) and 240.2 g ofisopropanol were added to a flask with a stir bar and stopper. The flaskwas heated to 40° C. to form a solution. The solution was then polishfiltered and transferred to a reactor at 40° C. with agitator, nitrogenline, thermocouple and cooling water, using 59.8 g of isopropanol torinse the flask and polish filter. 300.4 g of heptane was added and thesolution agitated. The reactor was cooled to a jacket temperature of 35°C. and 6.91 g of isopropanol was added to the reactor drop wise tocreate a clear solution. The solution was agitated and then seeded with602 mg ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(Form A′) and then agitated. The reactor was then cooled to 20° C. andagitated. 1399.86 g of heptane was added using an external pump.Following agitation, the slurry was filtered, washed with 15:85isopropanol:heptane and dried. 281.03 g ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof crystal Form A′ having greater than 97% chiral purity, and greaterthan 98% chemical purity, was obtained, representing a yield of about91%.

An NMR spectrum of theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideobtained in Example 11 is illustrated in FIG. 14, having the followingcharacteristics: ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.12-1.23 (m, 6H)1.57-1.66 (m, 1H) 1.68-1.80 (m, 2H) 1.95 (dq, J=12.18, 8.33 Hz, 1H)2.20-2.36 (m, 2H) 2.68 (dtd, J=8.61, 6.26, 6.26, 3.91 Hz, 1H) 2.91 (dq,J=12.08, 7.32 Hz, 1H) 3.12-3.27 (m, 3H) 3.32-3.48 (m, 1H) 3.60 (dd,J=13.30, 3.91 Hz, 1H) 3.97 (s, 3H) 6.49 (s, 1H) 8.28 (s, 1H).

Referring to FIGS. 12A-12C, FIGS. 12A-12C present data on theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,(S)-amisulpride, of crystal Form A′ obtained in Example 11. FIG. 12A isa DSC thermogram for crystal Form A′ of (S)-amisulpride obtained inExample 11; FIG. 12B a XRPD pattern for crystal Form A′ of(S)-amisulpride obtained in Example 11; and FIG. 12C a micrograph imageshowing crystals of crystal Form A′ of the (S)-amisulpride obtained inExample 11.

Example 12: General Overview of Preparation ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide

In overview,R-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A can be prepared in two steps: Step 1 Preparation of Crude(R)-amisulpride; and Step 2 Recrystallization of the Crude(R)-amisulpride to crystalline (R)-amisulpride of Form A.

Step 1, Examples 12 and 13

Step 1 in general comprises mixing4-Amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with ethyl chloroformateand then reacting with (R)-(1-ethyl pyrrolidin-2-yl)methanamine to formR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidehydrochloride. Other coupling reagents such as methyl, isopropyl andisobutyl chloroformates and dimethoxytriazinechloride are also suitablefor carrying out the coupling reaction. The resulting product isextracted into water and washed with ethyl acetate. TheR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidehydrochloride is converted to freebase, dissolved into ethyl acetate andwashed with base and water. The ethyl acetate solution is then dried andconcentrated. The ethyl acetate solvate ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidecrystallizes and is converted toR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) by the addition of methyl-tert butyl ether. TheR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) is then isolated by filtration.

Step 2, Examples 12 and 13

Step 2 in general comprises dissolving theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) of Step 1 into isopropanol and polish filtering. Theisopropanol solution is concentrated, diluted with n-heptane and seededwith Form A to yieldR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase crystals. The mixture is then cooled and filtered to yieldcrystallineR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidesubstantially of Form A.

It is to be understood that during the crystallization ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) the amount of water in the ethyl acetate solventaffects the crystallization and is preferably less than 0.5%.Accordingly the water content is preferably monitored during thedistillation of the ethyl acetate solution, such as for example bycoulometric titration (Karl Fischer). For example, in variousembodiments coulometric titration (Karl Fischer) was performed bynon-aqueous, perchloric acid titration where approximately 300 mg ofsample, accurately weighed, was dissolved in about 50 mL of glacialacetic acid and titrated with 0.1 N perchloric acid and the end-pointdetermined potentiometrically. The weight of sample was corrected forwater content and residual solvent content prior to assay calculation.The drying of the isolated solid is also preferably monitored. Invarious embodiments, the reaction of Step 1 is considered complete whenthe amount of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid in thereaction mixture is less than or equal to 10 A % (where A % refers toArea % by HPLC) and/or when the amount of4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid in the reaction mixtureis less than or equal to 10 mol %.

Example 13: Detailed Overview of Preparation ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A

Step 1: To a mixture of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acidin acetone at −10° C. and ethyl chloroformate, 4-methylmorpholine isadded at a rate (exothermic) so as to maintain the internal temperaturebelow −5° C. The reaction is stirred for 1 hour at −10° C. and then(R)-(1-ethyl pyrrolidin-2-yl)methanamine is added. After stirring for 2hours the reaction mixture is concentrated and diluted with water andethyl acetate. The ethyl acetate layer is removed and the aqueous layeris basified with potassium carbonate. Ethyl acetate is added and theaqueous layer removed. The organic layer is washed with water twice andconcentrated. The mixture is diluted with ethyl acetate and concentrateduntil water content of the ethyl acetate solution is below 0.5%. Thesolution is seeded at 31° C. with 1 wt % Form A and stirred at thenucleation temperature for 2 h. The mixture is cooled to 20° C. andstirred for 1 h. The slurry is diluted with methyl tert butylether(MtBE) and stirred for 2 h at 20 C. The suspension is filtered and theproduct cake is washed with MtBE/ethyl acetate. The wet-cake is driedunder vacuum at 40° C. 5° C. to constant weight to yieldR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude).

Step 2: Isopropanol andR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude) are mixed together. The mixture is heated to 50° C. to achievedissolution and then passed through a filter. The filtrate isconcentrated and cooled to 40° C. n-Heptane is added and the resultingsolution is cooled to 28° C. and seeded with Form A. The resultingslurry is cooled to 23° C. and stirred for 1.5 h at this temperature.More n-heptane is added and the slurry is stirred at 22° C. for 13 h.The suspension is filtered and the product cake is washed withisopropanol/N-heptane. The wet-cake is dried under vacuum at 40° C. 5°C. to constant weight to yieldR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A.

An NMR spectrum of theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A obtained by the methods of Examples 12 and 13 is illustratedin FIG. 15A, and FIG. 15B provides the number scheme used for theassignments of Table 48 based on the NMR spectrum of FIG. 15A, where thefollowing notation is used in Table 48: s: singlet, d: doublet, br s:broad singlet, br d broad doublet, ddd: doublet of doublets of doublets,t: triplet, q: quadruplet; m: multiplet, tt: triplet of triplets; dq:doublet of quadruplets.

TABLE 48 Assignment of ¹H NMR Spectrum of FIG. 15A Carbon Chemical (seeFIG. 15B) Shift Details 1 1.19-1.20 t, J = 7.24 Hz, 3 H 2 3.02-3.08 q, J= 7.43 Hz, 2 H 5 6.28 s, 1 H 8 8.45 s, 1 H 10a, b 3.18-3.23 ddd, J =13.50, 4.89, 2.74 Hz, 1 H 3.60-3.66 ddd, J = 13.69, 7.04, 2.74 Hz, 1 H11 2.53-2.64 m, 1 H 12a, b 1.52-1.59 m, 1 H 1.79-1.85 m, 1 H 131.64-1.69 m, 2 H 14a, b 2.09-2.15 m, 1 H 3.12-3.17 m, 1 H 15a, b2.18-2.21 m, 1 H 2.74-2.81 dq, J = 11.93, 7.37 Hz, 1 H 16 1.04-1.06 t, J= 7.04 Hz, 3 H 17 3.88 s, 3 H 18 5.71 s, 2 H 19 8.05-8.07 br dd, J =7.04, 2.35 Hz, 1 H

A ¹³C NMR spectrum of theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A obtained by the methods of Examples 12 and 13 is illustratedin FIG. 16A, and FIG. 16B provides the number scheme used for theassignments of Table 49 based on the ¹³C NMR spectrum of FIG. 16A.

TABLE 49 Assignment of ¹³C NMR Spectrum of FIG. 16A Chemical AssignmentShift (ppm) (see FIG. 16B) 7.15 1 49.45 2 112.24 3 111.83 4 98.53 5162.44 6 150.84 7 136.04 8 164.17 9 41.29 10 62.14 11 28.39 12 22.82 1353.54 14 47.82 15 14.14 16 56.03 17

Example 14: General Overview of Preparation ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide

In overview,S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′ can be prepared in two steps: Step 1 Preparation of Crude(S)-amisulpride; and Step 2 Recrystallization of the Crude(S)-amisulpride to crystalline (S)-amisulpride of Form A′.

Step 1, Examples 14 and 15

Step 1 in general comprises reacting4-Amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with ethyl chloroformateand then adding (S)-(1-ethyl pyrrolidin-2-yl)methanamine to formS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidehydrochloride. The resulting product is extracted into water and washedwith ethyl acetate.S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidehydrochloride is converted to freebase by the addition of aqueouspotassium carbonate, dissolved into ethyl acetate and washed with water.The ethyl acetate solution is dried and concentrated. The ethyl acetatesolvate ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidecrystallizes and is desolvated by the addition of methyl-tert butylether. TheS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) is isolated by filtration.

Step 2, Examples 14 and 15

Step 2 in general comprises dissolving theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) of into isopropanol and polish filtering. Theisopropanol solution is concentrated, diluted with n-heptane and seededwith Form A′ to yield a slurry ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide.The mixture is cooled and filtered to yield crystallineS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidesubstantially of Form A′.

It is to be understood that during the crystallization ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) the amount of water in the ethyl acetate solventaffects the crystallization and is preferably less than 0.5%.Accordingly the water content is preferably monitored during thedistillation of the ethyl acetate solution, such as for example bycoulometric titration (Karl Fischer). For example, in variousembodiments coulometric titration (Karl Fischer) was performed bynon-aqueous, perchloric acid titration where approximately 300 mg ofsample, accurately weighed, was dissolved in about 50 mL of glacialacetic acid and titrated with 0.1 N perchloric acid and the end-pointdetermined potentiometrically. The weight of sample was corrected forwater content and residual solvent content prior to assay calculation.The drying of the isolated solid is also preferably monitored. Invarious embodiments, the reaction of Step 1 is considered complete whenthe amount of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid in thereaction mixture is less than or equal to 10 A % (where A % refers toArea % by HPLC) and/or when the amount of4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid in the reaction mixtureis less than or equal to 10 mol %.

Example 15: Detailed Overview of Preparation ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′

Step 1: To a solution of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acidin acetone at −10° C. is added ethyl chloroformate. 4-Methylmorpholineis added at a rate (exothermic) so as to maintain the internaltemperature below −5° C. The reaction is stirred for 1 hour at −10° C.and then (S)-(1-ethyl pyrrolidin-2-yl)methanamine is added. Afterstirring for 2 hours the reaction mixture is concentrated and dilutedwith water and ethyl acetate. The ethyl acetate layer is removed and theaqueous layer is basified with potassium carbonate. Ethyl acetate isthen added and the aqueous layer removed. The organic layer is washedwith water twice and concentrated. The mixture is diluted with ethylacetate and concentrated until the water content of the ethyl acetatesolution is below 0.5%. The solution is seeded at 31° C. with 1 wt %S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′ and stirred at the nucleation temperature for 2 h. Themixture is cooled to 20° C. and stirred for 1 h. The slurry is thendiluted with methyl tert butylether (MtBE) and stirred for 2 h at 20° C.The suspension is then filtered and the product cake is washed withMtBE/ethyl acetate. The wet-cake is dried under vacuum at 40° C. 5° C.to constant weight to yieldS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude).

Step 2: Isopropanol is added toS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude) and the mixture is heated to 50° C. to achieve dissolution. Theresulting solution is then passed through a filter. The filtrate isconcentrated and cooled to 40° C. n-Heptane is then added and theresulting solution is cooled to 28° C. and seeded. The resulting slurryis cooled to 23° C. and stirred for 1.5 h at this temperature. Moren-heptane is added and the slurry is stirred at 22° C. for 13 h. Thesuspension is then filtered and the product cake is washed withisopropanol/n-heptane. The wet-cake is dried under vacuum at 40° C. 5°C. to constant weight to yieldS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidesubstantially of Form A′.

An NMR spectrum of theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′ obtained by the methods of Examples 14 and 15 is illustratedin FIG. 17A, and FIG. 17B provides the number scheme used for theassignments of Table 50 based on the NMR spectrum of FIG. 17A, where thefollowing notation is used in Table 50: s: singlet, d: doublet, br s:broad singlet, br broad doublet, ddd: doublet of doublets of doublets,t: triplet, q: quadruplet; m: multiplet, tt: triplet of triplets; dq:doublet of quadruplets.

TABLE 50 Assignment of 1-E1 NMR Spectrum of FIG. 17A Carbon Chemical(see FIG. 17B) Shift Details  1 1.21-1.25 t, J = 7.43 Hz, 3 H  23.05-3.11 q, J= 7.30 Hz, 2 H  5 6.20 s, 1 H  8 8.50 s, 1 H 10a, b3.22-3.26 ddd, J = 13.69, 4.89, 2.93 Hz, 1 H 3.64-3.70 ddd, J = 13.69,7.04, 2.74 Hz, 1 H 11 2.57-2.61 m, 1 H 12a, b 1.57-1.64 m, 1 H 1.83-1.88m, 1 H 13 1.66-1.72 m, 2 H 14a, b 2.12-2.16 m, 1 H 3.13-3.18 m, 1 H 15a,b 2.19-2.23 m, 1 H 2.79-2.84 dq, J = 12.13, 7.43 Hz, 1 H 16 1.07-1.11 t,J = 7.24 Hz, 3 H 17 3.91 s, 3 H 18 5.51 br s, 2 H 19 8.02-8.03 br d, J =5.1 Hz, 1 H

A ¹³C NMR spectrum of theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-metoxybenzamide of Form A′ obtained by the methods ofExamples 14 and 15 is illustrated in FIG. 18A, and FIG. 18B provides thenumber scheme used for the assignments of Table 51 based on the ¹³C NMRspectrum of FIG. 18A.

TABLE 51 Assignment of ¹³C NMR Spectrum of FIG. 18A Chemical AssignmentShift (ppm) (see FIG. 18 B) 7.23 1 49.67 2 112.81 3 112.30 4 98.44 5162.41 6 150.54 7 136.35 8 164.05 9 41.31 10 62.23 11 28.43 12 22.90 1353.63 14 47.89 15 14.23 16 56.00 17

The present inventions also include the following aspects andembodiments.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when administered to a subject population, thepharmaceutical composition results in a maximum QT interval prolongationrelative to baseline over the time period of 12 hours afteradministration that, compared to an immediate release composition havingthe same total daily amount of amisulpride as the pharmaceuticalcomposition, is (a) at least about 75% less than that of said immediaterelease composition; (b) at least about 65% less than that of saidimmediate release composition; (c) at least about 60% less than that ofsaid immediate release composition; (d) at least about 55% less thanthat of said immediate release composition; or (e) at least about 50%less than that of said immediate release composition. In variousembodiments, the maximum QT interval prolongation relative to baselineis the population average maximum QTcF interval prolongation relative tobaseline.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when said pharmaceutical composition is administered to asubject population it is effective to provide in the subject afteradministration an occupancy of dopamine D2 receptors that, compared toan immediate release composition having the same total daily amount ofamisulpride as the pharmaceutical composition, is (a) at least 85% ofthe dopamine D2 receptors occupancy of said immediate releasecomposition; (b) at least 90% of the dopamine D2 receptors occupancy ofsaid immediate release composition; or (c) at least 95% of the dopamineD2 receptors occupancy of said immediate release composition.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when said pharmaceutical composition is administered to asubject population effective to provide in the subject afteradministration: (1) an occupancy of dopamine D2 receptors between (a)about 20% and about 60% at about 27 hours after administration; or (b)about 20% and about 60% at about 27 hours after administration; and (2)an occupancy of dopamine D2 receptors that is substantially similar tothat achieved by an immediate release composition having the same totaldaily amount of amisulpride as the pharmaceutical composition.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when said pharmaceutical composition is administered to asubject population it provides, compared to an immediate releasecomposition having the same total daily amount of amisulpride as thepharmaceutical composition, a blood plasma Cmax of amisulpride that is(a) less than about 75% of the Cmax of said immediate releasecomposition; (b) less than about 65% of the Cmax of said immediaterelease composition; (c) is less than about 60% of the Cmax of saidimmediate release composition; (d) less than about 55% of the Cmax ofsaid immediate release composition; or (e) less than about 50% of theCmax of said immediate release composition.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein said pharmaceutical composition when administered to asubject population is effective in minimizing the difference betweenCmin and Cmax of amisulpride compared to an immediate releasecomposition having the same total daily amount of amisulpride as thepharmaceutical composition, wherein the value of Cmin is that at about 9hours after administration.

It is to be understood that in each of the aspects above, provided areembodiments wherein the immediate release composition having the sametotal daily amount of amisulpride as the pharmaceutical composition isthe immediate release composition described in Table 25 and having thesame total daily amount of amisulpride as the pharmaceuticalcomposition.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when administered to a subject population, saidpharmaceutical composition results in a maximum QT intervalprolongation, over the time period of 12 hours after administration, of(a) less than about 0.45 milliseconds (ms) per 10 mg of amisulpride; (b)less than about 0.40 milliseconds (ms) per 10 mg of amisulpride; (c)less than about 0.35 milliseconds (ms) per 10 mg of amisulpride; (d)less than about 0.30 milliseconds (ms) per 10 mg of amisulpride; (e)less than about 0.25 milliseconds (ms) per 10 mg of amisulpride; (f)less than about 0.20 milliseconds (ms) per 10 mg of amisulpride; (g)less than about 0.15 milliseconds (ms) per 10 mg of amisulpride; (h)less than about 0.10 milliseconds (ms) per 10 mg of amisulpride; (i)less than about 0.05 milliseconds (ms) per 10 mg of amisulpride; or (j)less than about 0.02 milliseconds (ms) per 10 mg of amisulpride. Invarious embodiments, the maximum QT interval prolongation relative tobaseline is the population average maximum QTcF interval prolongationrelative to baseline.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, about 200 mg ofamisulpride in the form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when administered to a subject population, saidpharmaceutical composition results in a population maximum QTcF intervalprolongation relative to baseline of (a) less than about 10 milliseconds(ms) over the time period of 12 hours after administration; (b) lessthan about 9 milliseconds (ms) over the time period of 12 hours afteradministration; (c) less than about 8 milliseconds (ms) over the timeperiod of 12 hours after administration; (d) less than about 7milliseconds (ms) over the time period of 12 hours after administration;(e) less than about 6 milliseconds (ms) over the time period of 12 hoursafter administration; or (f) less than about 5 milliseconds (ms) overthe time period of 12 hours after administration. In variousembodiments, the maximum QTcF interval prolongation relative to baselineis the population average maximum QTcF interval prolongation relative tobaseline.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, about 200 mg ofamisulpride in the form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when administered to a subject population, saidpharmaceutical composition is effective to provide at geometric meanCmax a QTcF interval prolongation relative to baseline that is (a) lessthan about 10 milliseconds (ms); (b) less than about 9 milliseconds(ms); (c) less than about 8 milliseconds (ms); (d) less than about 7milliseconds (ms); (e) is less than about 6 milliseconds (ms); or (f)less than about 5 milliseconds (ms). In various embodiments, the maximumQTcF interval prolongation relative to baseline is the populationaverage maximum QTcF interval prolongation relative to baseline.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when said composition is administered to a subjectpopulation it provides a Cmax/Cmin ratio of amisulpride, wherein thevalue of Cmin is determined within about 9 hours after administration,that is (a) less than about 2; (b) less than about 1.9; or (c) less thanabout 1.8. In various embodiments, (a) the values of Cmax and Cmin aredetermined within about 9 hours after administration; and/or (b) thevalue of Cmin is that at about 9 hours after administration.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when said pharmaceutical composition is administered to asubject population (i) the area under the curve (AUC) of blood plasmaconcentration versus time of amisulpride from administration to Tmax(AUC_(0-Tmax)) is less than about 19% of the area under the curve fromadministration to about 48 hours (AUC₀₋₄₈); and (ii) Tmax of amisulprideis between about 4 hours and about 6 hours after administration.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when a solid oral dosage form is administered to asubject population the the population mean time to Cmax (Tmax) ofamisulpride is between about 4 hours and about 6 hours afteradministration and the area under the curve (AUC) of blood plasmaconcentration versus time of amisulpride from administration to Tmax(AUC_(0-Tmax)) is (a) less than about 18% of the area under the curvefrom administration to 48 hours (AUC₀₋₄₈); (b) less than about 17% ofAUC₀₋₄₈; (c) less than about 15% of AUC₀₋₄₈; or (d) less than about 13%of AUC₀₋₄₈.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein the solid oral dosage form when dissolution tested usinga two-stage in vitro gastrointestinal simulation dissolution test (a)releases less than about 30% of the amisulpride after 1 hour, releasesmore than about 20% and less than about 60% of the amisulpride after 3hours, and releases more than about 30% and less than about 100% of theamisulpride after 6 hours; (b) releases less than about 30% of theamisulpride after 1 hour, releases more than 20% and less than about 60%of the amisulpride after 3 hours, and releases more than about 30% andless than 75% of the amisulpride after 6 hours; (c) releases less thanabout 20% of the amisulpride after 1 hour, releases more than about 20%and less than about 50% of the amisulpride after 3 hours, and releasesmore than about 30% and less than about 75% of the amisulpride after 6hours; (d) releases more than about 30% and less than about 50% of theamisulpride after 6 hours; (e) releases no more than about 30% of theamisulpride after 1 hour, releases between about 30% and about 75% ofthe amisulpride after about 3 hours, and releases more than about 75% ofthe amisulpride after about 12 hours; and/or (f) releases more thanabout 75% of the amisulpride after about 6 hours.

It is to be understood that in each of the aspects above, provided areembodiments wherein (a) the two-stage gastrointestinal simulationdissolution test comprises in the first stage 500 ml of an aqueous mediahaving a pH of about 2 and adding after 1 hour 400 ml of an aqueousbuffer media such that the second stage pH is 6.8; where the temperaturein both stages of the two-stage in vitro gastrointestinal simulationdissolution test is about 37° C.; and/or (b) wherein the two-stagegastrointestinal simulation dissolution test is conducted in a paddleapparatus substantially in accord with that described in one of more of:(a) United States Pharmacopeia Convention (USP) Apparatus 2 of Chapter711 Dissolution; USP41-NF36 General Chapter <711> Dissolution, and (b)Japanese Pharmacopeia (P) General test <6.10>.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form for reducing QT interval prolongation, the solid oraldosage form comprising, amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride; and one or morepharmaceutically acceptable excipients, wherein said solid oral dosageform is formulated for extended release. In various embodiments, thesolid oral dosage form when dissolution tested using the two-stage invitro dissolution test described in Table 5 in the paddle apparatusdescribed in United States Pharmacopeia Convention (USP) Apparatus 2 ofChapter 711 Dissolution; USP41-NF36 General Chapter <711> Dissolutionhas a dissolution profile substantially the same as (a) the profile ofLot 3C in FIG. 1C; or (b) the profile of Lot 2C in FIG. 1C.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein the solid oral dosage form when dissolution tested usingthe two-stage in vitro dissolution test described in Table 5 in thepaddle apparatus described in United States Pharmacopeia Convention(USP) Apparatus 2 of Chapter 711 Dissolution; USP41-NF36 General Chapter<711> Dissolution has a dissolution profile substantially the same as(a) the profile of Lot 3C in FIG. 1C; (b) the profile of Lot 2C in FIG.1C; (c) the profile of Lot 3Z used in the study of Example 7A, Part 1 orPart 2 in FIG. 1D; (d) the profile of Lot 3Z used in fed state study ofExample 7A, Part 1 in FIG. 1D; (e) the profile of Lot 3Z used in MAD/PETstudy of Example 7B in FIG. 1D; (f) the profile of Lot 4Z in FIG. 1D;(g) the profile of Lot 5Z in FIG. 1D; (h) the profile of Lot 6Z in FIG.1D; (i) the profile of Lot 7C in FIG. 1E over the time period from 0 to6 hours; (j) the profile of Lot 8C in FIG. 1E over the time period from0 to 6 hours; (k) the profile of Lot 7C in FIG. 1E over the time periodfrom 0 to 6 hours; (1) the profile of Lot 8C in FIG. 1E over the timeperiod from 0 to 6 hours.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and an extended release agent, wherein the solidoral dosage form when dissolution tested using the two-stage in vitrodissolution test described in Table 5 in the paddle apparatus describedin United States Pharmacopeia Convention (USP) Apparatus 2 of Chapter711 Dissolution; USP41-NF36 General Chapter <711> Dissolution has adissolution profile substantially the same as the profile of Lot 3Z usedin the study of one or more of (a) Example 7B; (b) Example 7A Part 1; or(c) Example 7A Part 2 in FIG. 1D.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when said pharmaceutical composition is administered to asubject population it provides a plasma concentration profilesubstantially the same as (a) the profile of Lot 4Z in FIG. 22B; or (b)the profile of Lot 4Z in FIG. 22F

In various aspects and embodiments, provided are pharmaceuticalcompositions in a solid oral dosage form, the solid oral dosage formcomprising, amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride; and one or morepharmaceutically acceptable excipients, the one or more excipientscomprising an extended release agent, wherein when said pharmaceuticalcomposition is administered to a subject population it provides a plasmaconcentration profile substantially the same as (a) the profile of Lot3Z in FIG. 22C; (b) the profile of Lot 3Z Fed State in FIG. 22D; (c) theprofile of Lot 3Z in FIG. 22H; (d) the profile of Lot 3Z Fed State inFIG. 22I; or (e) the profile of Lot 3Z in FIG. 22J.

In various aspects and embodiments, provided are pharmaceuticalcompositions in a solid oral dosage form, the solid oral dosage formcomprising, amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride; and one or morepharmaceutically acceptable excipients, the one or more excipientscomprising an extended release agent, wherein when said pharmaceuticalcomposition is administered to a subject population it provides a plasmaconcentration profile substantially the same as (a) the profile of Lot5Z in FIG. 22G; or (b) the profile of Lot 6Z in FIG. 22K.

It is to be understood that in each of the aspects above, provided areembodiments wherein the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is (a) from about 65:35 to about 88:12 by weight offree base; (b) from about 75:25 to about 88:12 by weight of free base;(c) from about 80:20 to about 88:12 by weight of free base; (d) fromabout 85:15 to about 90:10 by weight of free base; or (e) is about 85:15by weight of free base.

It is to be understood that in each of the aspects above, provided areembodiments wherein the amisulpride is in (a) an amount from about 85 mgto about 600 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptablesalt thereof, by weight of free base; and an amount from about 15 mg toabout 100 mg of (S)-(−)-amisulpride, or a pharmaceutically acceptablesalt thereof, by weight of free base; (b) an amount from about 170 mg toabout 340 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptablesalt thereof, by weight of free base; and an amount from about 30 mg toabout 60 mg of (S)-(−)-amisulpride, or a pharmaceutically acceptablesalt thereof, by weight of free base; (c) about 85 mg of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base; and about 15 mg of (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base; (d)about 170 mg of (R)-(+)-amisulpride, or a pharmaceutically acceptablesalt thereof, by weight of free base; and about 30 mg of(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base; or (e) about 340 mg of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base; andabout 60 mg of (S)-(−)-amisulpride, or a pharmaceutically acceptablesalt thereof, by weight of free base.

It is to be understood that in each of the aspects above, provided areembodiments wherein, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, is(a) about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500mg, about 600 mg or about 700 mg by weight of free base; (b) from about50 mg to about 1000 mg by weight of free base; (c) about 200 mg to about600 mg by weight of free base; (d) from about 100 mg to about 500 mg byweight of free base; (e) from about 200 mg to about 400 mg by weight offree base; (f) about 200 mg to about 700 mg by weight of free base; (g)about 100 mg by weight of free base; (h) about 160 mg by weight of freebase; (i) about 200 mg by weight of free base (j) about 300 mg by weightof free base; (k) about 400 mg by weight of free base; (1) about 500 mgby weight of free base; (m) about 600 mg by weight of free base; or (n)about 700 mg by weight of free base.

It is to be understood that in each of the aspects above, provided areembodiments wherein the solid oral dosage form comprises: a granularcomponent admixed with an extra-granular component, the granularcomponent comprising amisulpride and a binder; and the extra-granularcomponent comprising, an extended release agent. In various embodiments,(a) the extragranular component further comprises a filler; (b) theextended release agent comprises a biopolymer; and/or (c) the biopolymercomprises hypromellose. In various embodiments, (a) the extended releaseagent in an amount between about 10% and about 50% by total dosage formweight; (b) the extended release agent comprises hypromellose in anamount between about 10% and about 50% by total dosage form weight; (c)the amisulpride is in an amount between about 30% and about 50% by totaldosage form weight. In various embodiments, the granules comprise (a)between about 60% to about 80% by weight of amisulpride, between about10% to about 30% by weight of filler, and between about 1% to about 5%by weight of binder; (b) between about 70% to about 80% by weight ofamisulpride, between about 20% to about 25% by weight of filler, andbetween about 1% to about 5% by weight of binder. In variousembodiments, the granular component comprises: between about 73% toabout 78% by weight of amisulpride, between about 10% to about 12% byweight of a D-mannitol, between about 10% to about 12% by weight of apregelatinized starch, and between about 1% to about 3% by weight ofpolyvinyl alcohol, based on the weight of the granular component.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the solid oral dosage form is atablet. In various embodiments, the tablet (granules plus extragranularcomponent) comprises (a) between about 20% to about 70% by total tabletweight of granules of extended release agent; (b) between about 10% toabout 50% by total tablet weight of extended release agent; (c) acombined amount of filler in both granular and extragranular betweenabout 6% to about 60% by total tablet weight; (d) a combined amount offiller in both granular and extragranular between about 10% to about 50%by total tablet weight. In various embodiments, the tablet (granulesplus extragranular component) comprises between about 1% to about 2% bytotal tablet weight of a lubricant, and in various embodiments thelubricant is magnesium stearate. In various embodiments, the tablet(granules plus extragranular component) comprises (a) comprises betweenabout 34% to about 39% by total tablet weight of a D-mannitol, and about15% by total tablet weight of hypromellose; (b) between about 24% toabout 29% by total tablet weight of a D-mannitol, and about 25% by totaltablet weight of hypromellose; and/or (c) between about 4% to about 9%by total tablet weight of a D-mannitol, and about 45% by total tabletweight of hypromellose.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the pharmaceutical compositionis effective to provide after administration a maximum QT intervalprolongation, over the time period of 12 hours after administration, of(a) less than about 0.45 milliseconds (ms) per 10 mg of amisulpride; (b)less than about 0.30 milliseconds (ms) per 10 mg of amisulpride; (c)less than about 0.20 milliseconds (ms) per 10 mg of amisulpride; (d)less than about 0.15 milliseconds (ms) per 10 mg of amisulpride; (e)less than about 0.10 milliseconds (ms) per 10 mg of amisulpride; (f)less than about 0.05 milliseconds (ms) per 10 mg of amisulpride; or (g)less than about 0.02 milliseconds (ms) per 10 mg of amisulpride.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the pharmaceutical compositionis effective to provide a population maximum QTcF interval prolongationrelative to baseline of (a) less than about 10 milliseconds (ms) overthe time period of 12 hours after administration; (b) less than about 9milliseconds (ms) over the time period of 12 hours after administration;(c) less than about 8 milliseconds (ms) over the time period of 12 hoursafter administration; (d) less than about 7 milliseconds (ms) over thetime period of 12 hours after administration; (e) less than about 6milliseconds (ms) over the time period of 12 hours after administration;or (f) less than about 5 milliseconds (ms) over the time period of 12hours after administration. In various embodiments, the maximum QTcFinterval prolongation relative to baseline is the population averagemaximum QTcF interval prolongation relative to baseline.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the pharmaceutical compositionis effective to provide at geometric mean Cmax a QTcF intervalprolongation relative to baseline that is (a) less than about 10milliseconds (ms); (b) less than about 9 milliseconds (ms); (c) lessthan about 8 milliseconds (ms); (d) less than about 7 milliseconds (ms);(e) is less than about 6 milliseconds (ms); or (f) less than about 5milliseconds (ms).

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride; and one or more pharmaceutically acceptableexcipients, the one or more excipients comprising an extended releaseagent, wherein when said composition is administered to a subjectpopulation it provides a Cmax/Cmin ratio of amisulpride, wherein thevalue of Cmin is determined within about 9 hours after administration,that is (a) less than about 2; (b) less than about 1.9; or (c) less thanabout 1.8. In various embodiments, (a) the values of Cmax and Cmin aredetermined within about 9 hours after administration; and/or (b) thevalue of Cmin is that at about 9 hours after administration.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the pharmaceutical compositionis effective to provide after administration an occupancy of dopamine D2receptors of (a) about 20% to about 60%; or (b) about 30% to about 50%.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the pharmaceutical compositionwhen administered to a subject population provides a Tmax between about4 hours and about 6 hours after administration.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the modified release compositionwhen administered to a subject population provides a magnitude of QTprolongation that is less than that of a comparable immediate releasecomposition.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the modified release compositionwhen administered to a subject population provides a reduced incidenceof QT prolongation that is less than that of a comparable immediaterelease composition.

It is to be understood that in each of the aspects above, provided areembodiments wherein when a solid oral dosage form is administered to asubject population the area under the curve (AUC) of blood plasmaconcentration versus time of amisulpride from administration to Tmax(AUC_(0-Tmax)) is (a) less than about 18% of the area under the curvefrom administration to 48 hours (AUC₀₋₄₈); (b) less than about 17%AUC₀₋₄₈; (c) less than about 15% AUC₀₋₄₈; or (d) less than about 13% ofAUC₀₋₄₈.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, about 170 mg of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base; and about 30 mg of (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base; and anextended release agent, wherein when said pharmaceutical composition isadministered to a subject population it is effective to provide afteradministration: (a) maximum QTcF interval prolongation relative tobaseline is less than about 8 milliseconds (ms) over the time period of12 hours after administration; (b) an occupancy of dopamine D2 receptorsbetween about 20% and about 60% about 27 hours after administration; and(c) an occupancy of dopamine D2 receptors about 27 hours afteradministration that is at least 85% of the dopamine D2 receptorsoccupancy achieved by an immediate release composition having the sametotal daily amount of amisulpride as the pharmaceutical composition.

In various aspects, provided are pharmaceutical compositions in a solidoral dosage form, the solid oral dosage form comprising, amisulpride inthe form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride, and the amount of (S)-(−)-amisulpride is less thanabout 100 mg; and an extended release agent, wherein when said solidoral dosage form is administered to a subject population it is effectiveto provide in the subject about 27 hours after administration: (1) anoccupancy of dopamine D2 receptors between about 20% and about 60%; and;(2) an occupancy of dopamine D2 receptors that is at least 85% of thedopamine D2 receptors occupancy achieved by an immediate releasecomposition having the same total daily amount of amisulpride as thepharmaceutical composition.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments where applicable Cmax is (a) mean Cmax;(b) geometric mean Cmax; or (c) average Cmax. It is to be understoodthat in each of the embodiments and aspects above, provided areembodiments where applicable Cmin is (a) mean Cmin; (b) geometric meanCmin; or (c) average Cmin. It is to be understood that in each of theembodiments and aspects above, provided are embodiments where applicableTmax is (a) mean Tmax; (b) geometricamean Tmax; or (c) average Tmax. Itis to be understood that in each of the embodiments and aspects above,provided are embodiments where applicable maximum QT intervalprolongation is (a) mean maximum QT interval prolongation; (b) geometricmean maximum QT interval prolongation; or (c) average maximum QTinterval prolongation. It is to be understood that in each of theaspects above, provided are embodiments wherein when applicable the D2receptor occupancy is the average D2 receptor occupancy.

It is to be understood that in each of the aspects above, provided areembodiments wherein when applicable the occupancy of D2 receptors ismeasured using Positron Emission Tomography (PET) as described in Table38 and accompanying text.

It is to be understood that in each of the aspects above, provided areembodiments wherein the (R)-(+)-amisulpride is crystalline(R)-(+)-amisulpride of crystal Form A; and the (S)-(−)-amisulpride iscrystalline (S)-(−)-amisulpride of crystal Form A′; wherein Form A ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 15.4±0.2°; and Form A′ ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 15.4±0.2°.

In various aspects and embodiments, provided are methods of treating apsychiatric disorder in a subject comprising administering to thesubject a solid oral dosage form according to any of the aspects andembodiments of pharmaceutical compositions above and/or providing to asubject for the treatment of a psychiatric disorder a medicamentcomprising a pharmaceutical composition above. In various embodiments,the psychiatric disorder treated is (a) a depressive disorder; (b)bipolar disorder; (c) bipolar depression; (d) major depressive disorder(MDD); (e) major depressive disorder with mixed features (MDD-MF); (f)treatment resistant depression (TRD); (g) schizophrenia; (h) one or moreof schizophrenia and negative symptoms of schizophrenia; or (i) two ormore of schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression, bipolar disorder and depression.

In various aspects and embodiments, provided are methods of treating apsychiatric disorder in a subject comprising administering to thesubject a solid oral dosage form according to any of the aspects andembodiments of pharmaceutical compositions above and/or providing to asubject for the treatment of a psychiatric disorder a medicamentcomprising a pharmaceutical composition above wherein the psychiatricdisorder is selected from schizophrenia, negative symptoms ofschizophrenia, treatment resistant depression, bipolar disorder anddepression.

In various aspects and embodiments, provided are methods of treatingbipolar disorder comprising administering to a subject in need thereofan effective amount of a solid oral dosage form according to any of theaspects and embodiments of pharmaceutical compositions above and/orproviding to a subject for the treatment of a psychiatric disorder amedicament comprising a pharmaceutical composition above. In variousembodiments, the bipolar disorder is bipolar depression.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments of the methods above wherein the solidoral dosage form is effective to provide in the subject afteradministration (a) a suppression of the time in rapid eye movement (REM)sleep as characterized by a decrease in REM sleep by an amount greaterthan 10 minutes; (b) a suppression of the time in rapid eye movement(REM) sleep as characterized by a decrease in REM sleep by an amountabout 15 minutes to about 45 minutes; or (c) a suppression of the timein rapid eye movement (REM) sleep as characterized by a decrease in REMsleep by an amount about 15 minutes to about 30 minutes.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments of the methods above wherein the solidoral dosage form is effective to provide in the subject afteradministration (a) a suppression of the time in rapid eye movement (REM)sleep as characterized by a latency to REM sleep by an amount greaterthan 20 minutes; or (b) a suppression of the time in rapid eye movement(REM) sleep as characterized by a latency to REM sleep by an amountgreater than 30 minutes;

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments of the methods above wherein the solidoral dosage form is effective to provide in the subject afteradministration (a) a suppression of the time in rapid eye movement (REM)sleep as characterized by a decrease in total REM sleep time relative tototal sleep time by an amount greater than 5%; or (b) a suppression ofthe time in rapid eye movement (REM) sleep as characterized by adecrease in total REM sleep time relative to total sleep time by anamount greater than 6.5%.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein the pharmaceutical compositionis administered once daily. In various embodiments administrationcomprises administering once daily to a subject in need thereof aneffective amount of a pharmaceutical composition according to any one ofthe aspects and embodiments above.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein when said pharmaceuticalcomposition is first administered to a subject population it provides:(1) a blood plasma Cmax of amisulpride, compared to an immediate releasecomposition having the same total daily amount of amisulpride as thepharmaceutical composition, that is less than about 80% of the Cmax ofsaid immediate release composition; (2) a AUC from 0 to 24 hours afteradministration (AUC₀₋₂₄) of amisulpride, compared to an immediaterelease composition having the same total daily amount of amisulpride asthe pharmaceutical composition, that is (a) less than about 70% of theAUC₀₋₂₄ of said immediate release composition.

It is to be understood that in each of the embodiments and aspectsabove, provided are embodiments wherein when said pharmaceuticalcomposition is first administered to a subject population it provides:(1) a steady state blood plasma Cmax of amisulpride, compared to animmediate release composition having the same total daily amount ofamisulpride as the pharmaceutical composition, that is less than about80% of the Cmax of said immediate release composition; and (2) a steadystate AUC from 0 to 24 hours after administration (AUC₀₋₂₄) ofamisulpride, compared to an immediate release composition having thesame total daily amount of amisulpride as the pharmaceuticalcomposition, that is less than about 80% of the AUC₀₋₂₄ of saidimmediate release composition. In various embodiments, the steady stateblood plasma Cmax and steady state AUC are achieved after single dailydosage administration of the pharmaceutical composition over one week.

It is to be understood that in each of the aspects above, provided areembodiments wherein the solid oral dosage form provides atherapeutically effective plasma concentration over a period of 24 hoursto treat a psychiatric disorder when administered to a subject.

The present inventions also include the following aspects andembodiments. The following aspects and embodiments are listed withnumerical references for convenience in exposition and reference, suchnumerical listing and reference is not meant to be construed in alimiting sense.

Embodiment 1, a method of treating bipolar depression comprising:administering between about 200 mg to about 400 mg per day ofamisulpride by weight of free base as a solid oral dosage form to asubject, the solid oral dosage form comprising amisulpride in the formof an unequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the enantiomericratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is about 85:15 byweight of free base, and an extended release agent in an amount betweenabout 10% to about 50% by total solid oral dosage form weight; whereinsaid administration provides a subject population average maximum QTinterval prolongation relative to baseline that is less than 12milliseconds (ms).

Embodiment 2, the method of embodiment 1, wherein said administration isonce per day.

Embodiment 3, the method of embodiment 1, wherein said solid oral dosageform is a tablet.

Embodiment 4, the method of embodiment 1, wherein the population averagemaximum QT interval prolongation relative to baseline is the populationaverage maximum QTcF interval prolongation relative to baseline over thetime period of 12 hours after said administration.

Embodiment 5, the method of embodiment 1, wherein the population averagemaximum QT interval prolongation relative to baseline is less than 11milliseconds (ms).

Embodiment 6, the method of embodiment 1, wherein the population averagemaximum QT interval prolongation relative to baseline is less than 10milliseconds (ms).

Embodiment 7, the method of embodiment 1, wherein said administration isabout 200 mg per day of amisulpride by weight of free base.

Embodiment 8, the method of embodiment 7, wherein the population averagemaximum QT interval prolongation relative to baseline is less than 9milliseconds (ms).

Embodiment 9, the method of embodiment 1, wherein the extended releaseagent comprises a matrix forming agent.

Embodiment 10, the method of embodiment 9, wherein the matrix formingagent comprises one or more cellulosic ethers.

Embodiment 11, the method of embodiment 1, wherein the extended releaseagent is in an amount between about 20% to about 40% by total solid oraldosage form weight.

Embodiment 12, the method of embodiment 1, wherein the extended releaseagent comprises hydroxypropyl methylcellulose in an amount between about20% to about 30% by total solid oral dosage form weight.

Embodiment 13, the method of embodiment 1, wherein said administrationprovides about 27 hours after said administration a subject populationaverage occupancy of dopamine D2 receptors between about 20% and about60%, when the occupancy of D2 receptors is measured using PositronEmission Tomography (PET) substantially as described in Table 38 andaccompanying text.

Embodiment 14, the method of embodiment 1, wherein said administrationprovides: (a) a blood plasma population geometric mean Cmax ofamisulpride that is less than about 80% of the population geometric meanCmax achieved by an immediate release composition having the same totaldaily amount of amisulpride as the solid oral dosage form, and (b) apopulation geometric mean AUC from 0 to 24 hours after administration(AUC₀₋₂₄) of amisulpride that is less than about 80% of the populationgeometric mean AUC₀₋₂₄ achieved by an immediate release compositionhaving the same total daily amount of amisulpride as the solid oraldosage form.

Embodiment 15, the method of embodiment 14, wherein said immediaterelease composition is the immediate release composition substantiallyas described in Table 25 and having the same total daily amount ofamisulpride as the pharmaceutical composition.

Embodiment 16, a method of treating bipolar depression comprising:administering between about 200 mg to about 400 mg per day ofamisulpride by weight of free base as a tablet to a subject, the tabletcomprising amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight of freebase, and an extended release agent in an amount between about 10% toabout 50% by total tablet weight; wherein said administration provides asubject population average maximum QT interval prolongation relative tobaseline that is less than about 0.4 milliseconds (ms) per 10 mg ofamisulpride.

Embodiment 17, the method of embodiment 16, wherein said administrationis once per day.

Embodiment 18, the method of embodiment 16, wherein the populationaverage maximum QT interval prolongation relative to baseline is thepopulation average maximum QTcF interval prolongation relative tobaseline over the time period of 12 hours after said administration.

Embodiment 19, the method of embodiment 16, wherein the populationaverage maximum QT interval prolongation relative to baseline is lessthan about 0.35 milliseconds (ms) per 10 mg of amisulpride.

Embodiment 20, the method of embodiment 16, wherein the populationaverage maximum QT interval prolongation relative to baseline is lessthan about 0.3 milliseconds (ms) per 10 mg of amisulpride.

Embodiment 21, the method of embodiment 16, wherein the extended releaseagent comprises a matrix forming agent.

Embodiment 22, the method of embodiment 21, wherein the matrix formingagent comprises one or more cellulosic ethers.

Embodiment 23, the method of embodiment 22, wherein the extended releaseagent comprises hydroxypropyl methylcellulose in an amount between about20% to about 40% by total tablet weight.

Embodiment 24, the method of embodiment 16, wherein said administrationprovides about 27 hours after said administration a subject populationaverage occupancy of dopamine D2 receptors between about 20% and about60%, when the occupancy of D2 receptors is measured using PositronEmission Tomography (PET) substantially as described in Table 38 andaccompanying text.

Embodiment 25, the method of embodiment 16, wherein said administrationprovides a population Cmax/Cmin ratio of amisulpride that is less thanabout 2, wherein the values of Cmax and Cmin are determined within 9hours after administration.

Embodiment 26, the method of embodiment 16, wherein said administrationprovides: a. a blood plasma population geometric mean Cmax ofamisulpride that is less than about 80% of the population geometric meanCmax achieved by an immediate release composition having the same totaldaily amount of amisulpride as the pharmaceutical composition, and b. apopulation geometric mean AUC from 0 to 24 hours after administration(AUC₀₋₂₄) of amisulpride that is less than about 80% of the populationgeometric mean AUC₀₋₂₄ achieved by an immediate release compositionhaving the same total daily amount of amisulpride as the pharmaceuticalcomposition.

Embodiment 27, the method of embodiment 26, wherein said immediaterelease composition is the immediate release composition substantiallyas described in Table 25 and having the same total daily amount ofamisulpride as the pharmaceutical composition

Embodiment 28, a method of treating bipolar depression comprising:

administering between about 200 mg to about 400 mg per day ofamisulpride by weight of free base as a solid oral dosage form to asubject, the solid oral dosage form comprising amisulpride in the formof an unequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the enantiomericratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weightof free base, and an extended release agent in an amount between about10% to about 50% by total solid oral dosage form weight; wherein saidadministration provides: a subject population average maximum QTcFinterval prolongation relative to baseline that is less than 12milliseconds (ms) over the time period of 12 hours after saidadministration, and about 27 hours after said administration a subjectpopulation average occupancy of dopamine D2 receptors between about 20%and about 60%.

Embodiment 29, the method of embodiment 28, wherein said administrationis once per day.

Embodiment 30, the method of embodiment 28, wherein said solid oraldosage form is a tablet.

Embodiment 31, the method of embodiment 28, wherein the occupancy of D2receptors is measured using Positron Emission Tomography (PET)substantially as described in Table 38 and accompanying text.

Embodiment 32, the method of embodiment 28, wherein the extended releaseagent comprises a matrix forming agent.

Embodiment 33, the method of embodiment 32, wherein the matrix formingagent comprises one or more cellulosic ethers.

Embodiment 34, the method of embodiment 28, wherein the extended releaseagent comprises hydroxypropyl methylcellulose in an amount between about20% to about⁴⁰⁰/by total solid oral dosage form weight.

Embodiment 35, the method of embodiment 28, wherein said administrationprovides a population Cmax/Cmin ratio of amisulpride that is less thanabout 2, wherein the values of Cmax and Cmin are determined within 9hours after administration.

Embodiment 36, the method of embodiment 28, wherein said administrationprovides: a. a blood plasma population geometric mean Cmax ofamisulpride that is less than about 80% of the population geometric meanCmax achieved by an immediate release composition having the same totaldaily amount of amisulpride as the pharmaceutical composition, and b. apopulation geometric mean AUC from 0 to 24 hours after administration(AUC₀₋₂₄) of amisulpride that is less than about 80% of the populationgeometric mean AUC₀₋₂₄ achieved by an immediate release compositionhaving the same total daily amount of amisulpride as the pharmaceuticalcomposition.

Embodiment 37, the method of embodiment 36, wherein said immediaterelease composition is the immediate release composition substantiallyas described in Table 25 and having the same total daily amount ofamisulpride as the pharmaceutical composition

Embodiment 38, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of (R)-(+)amisulpride is greater than the amount of (S)-(−)-amisulpride; and oneor more pharmaceutically acceptable excipients, wherein whenadministered to a subject population, said pharmaceutical compositionprovides a population average maximum QT interval prolongation relativeto baseline over the time period of 12 hours after administration of:(a) less than about 0.45 milliseconds (ms) per 10 mg of amisulpride; or(b) less than about 0.40 milliseconds (ms) per 10 mg of amisulpride; or(c) less than about 0.35 milliseconds (ms) per 10 mg of amisulpride; or(d) less than about 0.30 milliseconds (ms) per 10 mg of amisulpride; or(e) less than about 0.25 milliseconds (ms) per 10 mg of amisulpride; or(f) less than about 0.20 milliseconds (ms) per 10 mg of amisulpride; or(g) less than about 0.15 milliseconds (ms) per 10 mg of amisulpride; or(h) less than about 0.10 milliseconds (ms) per 10 mg of amisulpride; or(i) less than about 0.05 milliseconds (ms) per 10 mg of amisulpride or(j) less than about 0.02 milliseconds (ms) per 10 mg of amisulpride.

Embodiment 39, the pharmaceutical composition of embodiment 38, whereinthe population average maximum QT interval prolongation relative tobaseline is the population average maximum QTcF interval prolongationrelative to baseline.

Embodiment 40, the pharmaceutical composition of embodiment 38, whereinthe combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is: (a) about 100 mg; or (b)about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400mg; or (f) about 500 mg; or (g) or about 600 mg by weight of free base.

Embodiment 41, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, 200 mg of amisulpride in the formof an unequal mixture of (R)-(+) amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride;and one or more pharmaceutically acceptable excipients, wherein whenadministered to a subject population provides a population averagemaximum QTcF interval prolongation relative to baseline over the timeperiod of 12 hours after administration of: (a) less than about 10milliseconds (ms); or (b) less than about 9 milliseconds (ms); or (c)less than about 8 milliseconds (ms); or (d) less than about 7milliseconds (ms); or (e) less than about 6 milliseconds (ms); or (f)less than about 5 milliseconds (ms).

Embodiment 42, the pharmaceutical composition of embodiment 41, whereinthe population average maximum QTcF interval prolongation relative tobaseline is the population average maximum QTcF interval prolongationrelative to baseline at geometric mean Cmax.

Embodiment 43, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of (R)-(+)amisulpride is greater than the amount of (S)-(−)-amisulpride; and oneor more pharmaceutically acceptable excipients, wherein whenadministered to a subject population, the pharmaceutical compositionprovides a population average maximum QT interval prolongation relativeto baseline over the time period of 12 hours after administration,compared to an immediate release composition having the same total dailyamount of amisulpride as the pharmaceutical composition, that is: (a) atleast about 75% less than that of said immediate release composition; or(b) at least about 65% less than that of said immediate releasecomposition; or (c) at least about 60% less than that of said immediaterelease composition; or (d) at least about 55% less than that of saidimmediate release composition; or (e) at least about 50% less than thatof said immediate release composition.

Embodiment 44, the pharmaceutical composition of embodiment 43, whereinthe population average maximum QT interval prolongation relative tobaseline is the population average maximum QTcF interval prolongationrelative to baseline.

Embodiment 45, the pharmaceutical composition of embodiment 43, whereinsaid immediate release composition is the immediate release compositionsubstantially as described in Table 25 and having the same total dailyamount of amisulpride as the pharmaceutical composition.

Embodiment 46, the pharmaceutical composition of embodiment 43, whereinthe combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is: (a) about 100 mg; or (b)about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400mg; or (f) about 500 mg; or (g) or about 600 mg by weight of free base.

Embodiment 47, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride;and one or more pharmaceutically acceptable excipients, wherein whensaid pharmaceutical composition is administered to a subject populationprovides at about 27 hours after administration a population averageoccupancy of dopamine D2 receptors that is: (a) at least 85% of thedopamine D2 receptors occupancy achieved by an immediate releasecomposition having the same total daily amount of amisulpride as thepharmaceutical composition; or (b) at least 90% of the dopamine D2receptors occupancy achieved by an immediate release composition havingthe same total daily amount of amisulpride as the pharmaceuticalcomposition; or (c) at least 95% of the dopamine D2 receptors occupancyachieved by an immediate release composition having the same total dailyamount of amisulpride as the pharmaceutical composition.

Embodiment 48, the pharmaceutical composition of embodiment 47, whereinsaid immediate release composition is the immediate release compositionsubstantially as described in Table 25 and having the same total dailyamount of amisulpride as the pharmaceutical composition.

Embodiment 49, the pharmaceutical composition of embodiment 47, whereinthe combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is: (a) about 100 mg; or (b)about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400mg; or (f) about 500 mg; or (g) or about 600 mg by weight of free base.

Embodiment 50, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,and one or more pharmaceutically acceptable excipients, wherein saidpharmaceutical composition when administered to a subject population iseffective in minimizing the difference between Cmin and Cmax ofamisulpride compared to an immediate release composition having the sametotal daily amount of amisulpride as the pharmaceutical composition,wherein the value of Cmin is determined within about 9 hours afteradministration.

Embodiment 51, the pharmaceutical composition of embodiment 50, whereinthe combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is: (a) about 100 mg; or (b)about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400mg; or (f) about 500 mg; or (g) or about 600 mg by weight of free base.

Embodiment 52, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,and one or more pharmaceutically acceptable excipients, wherein whensaid composition is administered to a subject population provides aCmax/Cmin ratio of amisulpride, wherein the value of Cmin is determinedwithin about 9 hours after administration, that is: (a) less than about2; or (b) less than about 1.9; or (c) less than about 1.8.

Embodiment 53, the pharmaceutical composition of embodiment 52, whereinthe values of Cmax and Cmin are the population geometric mean values andthe values are determined within about 9 hours after administration.

Embodiment 54, the pharmaceutical composition of embodiment 52, whereinthe solid oral dosage when administered in a total amount of amisulprideof 200 mg provides a blood plasma population geometric mean Cmax of (a)less than about 350 ng/mL; (b) less than about 300 ng/mL; or (c) lessthan about 250 ng/mL.

Embodiment 55, the pharmaceutical composition of embodiment 52, whereinthe solid oral dosage when administered in a total amount of amisulprideof 400 mg provides a blood plasma population geometric mean Cmax of (a)less than about 500 ng/mL; (b) less than about 475 ng/mL; or (c) lessthan about 450 ng/mL

Embodiment 56, the pharmaceutical composition of embodiment 52, whereinthe combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is: (a) about 100 mg; or (b)about 160 mg; or (c) about 200 mg; or (d) about 300 mg; or (e) about 400mg; or (f) about 500 mg; or (g) or about 600 mg by weight of free base.

Embodiment 57, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of (R)-(+)amisulpride is greater than the amount of (S)-(−)-amisulpride; and anextended release agent,

wherein the solid oral dosage form when dissolution tested using atwo-stage in vitro gastrointestinal simulation dissolution test: (a)releases less than about 30% of the amisulpride after 1 hour, releasesmore than about 20% and less than about 60% of the amisulpride after 3hours, and releases more than about 30% and less than about 100% of theamisulpride after 6 hours; or (b) releases less than about 30% of theamisulpride after 1 hour, releases more than 20% and less than about 60%of the amisulpride after 3 hours, and releases more than about 30% andless than 75% of the amisulpride after 6 hours; or (c) releases lessthan about 20% of the amisulpride after 1 hour, releases more than about20% and less than about 50% of the amisulpride after 3 hours, andreleases more than about 30% and less than about 75% of the amisulprideafter 6 hours; or (d) releases less than about 20% of the amisulprideafter 1 hour, releases more than about 20% and less than about 50% ofthe amisulpride after 3 hours, and releases more than about 30% and lessthan about 50% of the amisulpride after 6 hours; or (e) releases no morethan about 30% of the amisulpride after 1 hour, releases between about30% and about 75% of the amisulpride after about 3 hours, and releasesmore than about 75% of the amisulpride after about 12 hours; or (f)releases less than about 30% of the amisulpride after 1 hour, releasesmore than about 20% and less than about 60% of the amisulpride after 3hours, releases more than about 30% and less than about 100% of theamisulpride after 6 hours, and releases more than about 75% of theamisulpride after about 10 hours; or (g) releases less than about 30% ofthe amisulpride after 1 hour, releases more than about 20% and less thanabout 60% of the amisulpride after 3 hours, releases more than about 30%and less than about 100% of the amisulpride after 6 hours, and releasesmore than about 75% of the amisulpride after about 8 hours; or (h)releases less than about 30% of the amisulpride after 1 hour, releasesmore than about 20% and less than about 60% of the amisulpride after 3hours, releases more than about 30% and less than about 75% of theamisulpride after 6 hours, and releases more than about 75% of theamisulpride after about 10 hours; or (i) releases less than about 20% ofthe amisulpride after 1 hour, releases more than about 20% and less thanabout 60% of the amisulpride after 3 hours, releases more than about 30%and less than about 100% of the amisulpride after 6 hours, and releasesmore than about 75% of the amisulpride after about 10 hours; or (j)releases less than about 30% of the amisulpride after 1 hour, releasesmore than about 20% and less than about 60% of the amisulpride after 3hours, releases more than about 30% and less than about 50% of theamisulpride after 6 hours, and releases more than about 75% of theamisulpride after about 10 hours.

Embodiment 58, the pharmaceutical composition of embodiment 57, whereinthe two-stage gastrointestinal simulation dissolution test comprises inthe first stage 500 ml of an aqueous media having a pH of about 2 andadding after 1 hour 400 ml of an aqueous buffer media such that thesecond stage pH is 6.8; where the temperature in both stages of thetwo-stage in vitro gastrointestinal simulation dissolution test is about37° C.

Embodiment 59, the pharmaceutical composition of embodiment 57, whereinthe two-stage gastrointestinal simulation dissolution test is conductedin a paddle apparatus substantially in accord with that described in oneof more of: (a) United States Pharmacopeia Convention (USP) Apparatus 2of Chapter 711 Dissolution; USP41-NF36 General Chapter <711>Dissolution, and (b) Japanese Pharmacopeia (JP) General test <6.10>.

Embodiment 60, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride;and an extended release agent,

wherein the solid oral dosage form when dissolution tested using thetwo-stage in vitro dissolution test described in Table 5 in the paddleapparatus described in United States Pharmacopeia Convention (USP)Apparatus 2 of Chapter 711 Dissolution; USP41-NF36 General Chapter <711>Dissolution has a dissolution profile substantially the same as: (a) theprofile of Lot 3C in FIG. 1C; or (b) the profile of Lot 2C in FIG. 1C;or (c) the profile of Lot 3Z used in the study of Example 7A, Part 1 orPart 2 in FIG. 1D; or (d) the profile of Lot 3Z used in fed state studyof Example 7A, Part 1 in FIG. 1D; or (e) the profile of Lot 3Z used inMAD/PET study of Example 7B in FIG. 1D; or (f) the profile of Lot 4Z inFIG. 1D; or (g) the profile of Lot 5Z in FIG. 1D; or (h) the profile ofLot 6Z in FIG. 1D; or (i) the profile of Lot 7C in FIG. 1E over the timeperiod from 0 to 6 hours; or (j) the profile of Lot 8C in FIG. 1E overthe time period from 0 to 6 hours; or (k) the profile of Lot 3Z used inthe study of Example 7B, Example 7A Part 1, or (l) the profile of Lot 3Zused in the study of Example 7A Part 2 in FIG. 1D.

Embodiment 61, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of (R)-(+)amisulpride is greater than the amount of (S)-(−)-amisulpride; and anextended release agent,

wherein when said pharmaceutical composition is administered to asubject population provides a plasma concentration profile substantiallythe same as: (a) the profile of Lot 4Z in FIG. 22B; or (b) the profileof Lot 3Z in FIG. 22C; or (c) the profile of Lot 3Z Fed State in FIG.22D; (d) the profile of Lot 4Z in FIG. 22F; or (e) the profile of Lot 3Zin FIG. 22H; or (f) the profile of Lot 3Z Fed State in FIG. 22I; or (g)the profile of Lot 3Z in FIG. 22J; or (h) the profile of Lot 5Z in FIG.22G; or (i) the profile of Lot 6Z in FIG. 22K.

Embodiment 62, a pharmaceutical composition in a solid oral dosage form,the solid oral dosage form comprising, amisulpride in the form of anunequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, wherein the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride;and an extended release agent,

wherein when said solid oral dosage form is administered to a subjectpopulation provides: (i) a population geometric mean Tmax of amisulprideis between about 4 hours and about 6 hours after administration; and(ii) a AUC to Tmax (AUC_(0-Tmax)) that is less than about: (a) 19% ofthe area under the curve from administration to about 48 hours(AUC₀₋₄₈); or (b) 18% of the population mean area under the curve fromadministration to about 48 hours (AUC₀₋₄₈); or (c) 17% of the area underthe curve from administration to 48 hours (AUC₀₋₄₈); or (d) 16% of thearea under the curve from administration to 48 hours (AUC₀₋₄₈); or (e)15% of the area under the curve from administration to 48 hours(AUC₀₋₄₈); or (f) 14% of the area under the curve from administration to48 hours (AUC₀₋₄₈); or (g) 13% of the area under the curve fromadministration to 48 hours (AUC₀₋₄₈); or (h) 12% of the area under thecurve from administration to 48 hours (AUC₀₋₄₈).

Embodiment 63, the pharmaceutical composition of any one of embodiments40, 41, 46, 47, 51, and 56 wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is about 85:15 by weight of free base.

Embodiment 64, the pharmaceutical composition of embodiment 63, whereinthe one or more pharmaceutically acceptable excipients comprise anextended release agent.

Embodiment 65, the pharmaceutical composition of embodiment 64, whereinthe extended release agent is in an amount: (a) between about 10% andabout 50% by total solid oral dosage form weight; or (b) between about30% and about 50% by total solid oral dosage form weight; or (c) betweenabout 20% and about 40% by total solid oral dosage form weight; or (d)between about 20% and about 30% by total solid oral dosage form weight.

Embodiment 66, the pharmaceutical composition of embodiment 65, whereinthe solid oral dosage form is a tablet.

Embodiment 67, the pharmaceutical composition of embodiment 66, whereinthe extended release agent comprises a matrix forming agent.

Embodiment 68, the pharmaceutical composition of embodiment 67, whereinthe matrix forming agent comprises one or more cellulosic ethers.

Embodiment 69, the pharmaceutical composition of embodiment 66, whereinthe extended release agent comprises hydroxypropyl methylcellulose in anamount between about 20% to about 40% by total solid oral dosage formweight.

Embodiment 70, the pharmaceutical composition of embodiment 63, whereinthe solid oral dosage form comprises by total solid oral dosage formweight: between about 35% to about 45% of said amisulpride, betweenabout 20% to about 40% of a pharmaceutically acceptable filler, andbetween about 20% to about 35% of the extended release agent.

Embodiment 71, the pharmaceutical composition of embodiment 63, whereinwhen said pharmaceutical composition is administered to the subjectpopulation provides: (a) a blood plasma population geometric mean Cmaxof amisulpride that is less than about 80% of the population geometricmean Cmax achieved by an immediate release composition having the sametotal daily amount of amisulpride as the pharmaceutical composition, and(b) a population geometric mean AUC from 0 to 24 hours afteradministration (AUC₀₋₂₄) of amisulpride that is less than about 80% ofthe population geometric mean AUC₀₋₂₄ achieved by an immediate releasecomposition having the same total daily amount of amisulpride as thepharmaceutical composition.

Embodiment 72, the pharmaceutical composition of embodiment 71, whereinsaid immediate release composition is the immediate release compositionsubstantially as described in Table 25 and having the same total dailyamount of amisulpride as the pharmaceutical composition.

Embodiment 73, the pharmaceutical composition of embodiment 63, whereinwhen said pharmaceutical composition is administered to the subjectpopulation provides about 27 hours after said administration: (a) apopulation average occupancy of dopamine D2 receptors between about 20%and about 60%, or (b) a population average occupancy of dopamine D2receptors between about 30% and about 50%; wherein the occupancy of D2receptors is measured using Positron Emission Tomography (PET)substantially as described in Table 38 and accompanying text.

Embodiment 74, the pharmaceutical composition of embodiment 73, whereinthe amount of (S)-(−)-amisulpride, or pharmaceutically acceptable saltsthereof, is less than about 100 mg by weight of free base.

Embodiment 75, a method of treating a psychiatric disorder comprisingadministering a solid oral dosage form of embodiment 63.

Embodiment 76, the method of embodiment 75, wherein the solid oraldosage form is administered once per day in a total daily amount ofbetween about 200 mg to about 400 mg per day of said amisulpride byweight of free base.

Embodiment 77, the method of embodiment 76, wherein the psychiatricdisorder is: (a) a depressive disorder; or (b) bipolar disorder; or (c)bipolar depression; or (d) major depressive disorder (MDD); or (e) majordepressive disorder with mixed features (MDD-MF); or (f) treatmentresistant depression (TRD); or (g) schizophrenia; or (h) negativesymptoms of schizophrenia.

Embodiment 78, the method of embodiment 76, wherein the psychiatricdisorder is bipolar disorder; bipolar depression; or both.

Embodiment 79, a method of treating bipolar depression comprisingadministering a solid oral dosage form of embodiment 63 in once per dayin a total daily amount of between about 200 mg to about 400 mg per dayof said amisulpride by weight of free base.

Embodiment 80, a method of treating bipolar depression comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition of embodiment 63.

Embodiment 81, the pharmaceutical composition of any one of embodiments57, 60, 61, and 62, wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is about 85:15 by weight of free base.

Embodiment 82, the pharmaceutical composition of embodiment 81, whereinthe extended release agent is in an amount: (a) between about 10% andabout 50% by total solid oral dosage form weight; or (b) between about30% and about 50% by total solid oral dosage form weight; or (c) betweenabout 20% and about 40% by total solid oral dosage form weight; or (d)between about 20% and about 30% by total solid oral dosage form weight.

Embodiment 83, the pharmaceutical composition of embodiment 82, whereinthe solid oral dosage form is a tablet.

Embodiment 84, the pharmaceutical composition of embodiment 83, whereinthe extended release agent comprises a matrix forming agent.

Embodiment 85, the pharmaceutical composition of embodiment 83, whereinthe matrix forming agent comprises one or more cellulosic ethers.

Embodiment 86, the pharmaceutical composition of embodiment 83, whereinthe extended release agent comprises hydroxypropyl methylcellulose in anamount between about 20% to about 40% by total solid oral dosage formweight.

Embodiment 87, the pharmaceutical composition of embodiment 83, whereinthe solid oral dosage form comprises one or more of (a) a filler; (b) abinder; and (c) a lubricant.

Embodiment 88, the pharmaceutical composition of embodiment 87, whereinthe lubricant comprises magnesium stearate.

Embodiment 89, the pharmaceutical composition of embodiment 87, whereinthe filler comprises D-mannitol and wherein the solid oral dosage formcomprises between about 0.5% to about 2% by total tablet weight of abinder comprising polyvinyl alcohol.

Embodiment 90, the pharmaceutical composition of embodiment 81, whereinthe solid oral dosage form comprises by total solid oral dosage formweight: between about 35% to about 45% of said amisulpride, betweenabout 20% to about 40% of a pharmaceutically acceptable filler, andbetween about 20% to about 35% of the extended release.

Embodiment 91, the pharmaceutical composition of any one of embodiments38, 41, 43, 47, 50, 52, 57, 60, 61, and 62, wherein the enantiomericratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is from about: (a)65:35 to about 88:12 by weight of free base; or (b) 75:25 to about 88:12by weight of free base; or (c) 80:20 to about 88:12 by weight of freebase; or (d) 85:15 to about 90:10 by weight of free base.

Embodiment 92, the pharmaceutical composition of any one of embodiments38, 43, 47, 50, 52, 57, 60, and 62, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is from: (a) about 50 mg to about 600 mg byweight of free base; or (b) about 200 mg to about 600 mg by weight offree base; or (c) about 100 mg to about 500 mg by weight of free base;or (d) about 100 mg to about 400 mg by weight of free base; or (e) about200 mg to about 400 mg by weight of free base.

Embodiment 93, the pharmaceutical composition of embodiment 92,comprising: about 170 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and about 30 mg of(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base.

Embodiment 94, the pharmaceutical composition of embodiment 92,comprising: about 85 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and about 15 mg of(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base.

Embodiment 95, a pharmaceutical composition of any one of embodiments47, 50, 52, 57, 60, 61, and 62, wherein when administered to a subjectpopulation provides a population average maximum QT intervalprolongation relative to baseline over the time period of 12 hours afteradministration of: (a) less than about 0.45 milliseconds (ms) per 10 mgof amisulpride; or (b) less than about 0.40 milliseconds (ms) per 10 mgof amisulpride; or (c) less than about 0.35 milliseconds (ms) per 10 mgof amisulpride; or (d) less than about 0.30 milliseconds (ms) per 10 mgof amisulpride; or (e) less than about 0.25 milliseconds (ms) per 10 mgof amisulpride; or (f) less than about 0.20 milliseconds (ms) per 10 mgof amisulpride; or (g) less than about 0.15 milliseconds (ms) per 10 mgof amisulpride; or (h) less than about 0.10 milliseconds (ms) per 10 mgof amisulpride; or (i) less than about 0.05 milliseconds (ms) per 10 mgof amisulpride or (j) less than about 0.02 milliseconds (ms) per 10 mgof amisulpride.

Embodiment 96, a pharmaceutical composition of any one of embodiments38, 41, 43, 47, 50, 52, 57, 60, and 61, wherein, when administered to asubject population provides, compared to an immediate releasecomposition having the same total daily amount of amisulpride as thepharmaceutical composition, a blood plasma Cmax of amisulpride that is:(a) less than about 80% of the Cmax of said immediate releasecomposition; (b) less than about 75% of the Cmax of said immediaterelease composition; or (c) less than about 65% of the Cmax of saidimmediate release composition; or (d) is less than about 60% of the Cmaxof said immediate release composition; or (e) less than about 55% of theCmax of said immediate release composition; or (f) less than about 50%of the Cmax of said immediate release composition.

Embodiment 97, a pharmaceutical composition of any one of embodiments40, 41, 46, 47, 50, 56, 57, 60, 61, and 62, wherein, when administeredto a subject population provides a suppression of the time in rapid eyemovement (REM) sleep as characterized by: (a) a decrease in REM sleep byan amount greater than 10 minutes; or (b) a decrease in REM sleep by anamount about 15 minutes to about 45 minutes; or (c) a decrease in REMsleep by an amount about 15 minutes to about 30 minutes.

Embodiment 98, a pharmaceutical composition of any one of embodiments40, 41, 46, 47, 50, 56, 57, 60, 61, and 62, wherein, when administeredto a subject population provides a suppression of the time in rapid eyemovement (REM) sleep as characterized by: (a) a latency to REM sleep byan amount greater than 20 minutes; or (b) a latency to REM sleep by anamount greater than 30 minutes.

Embodiment 99, a pharmaceutical composition of any one of embodiments40, 41, 46, 47, 50, 56, 57, 60, 61, and 62, wherein, when administeredto a subject population provides a suppression of the time in rapid eyemovement (REM) sleep as characterized by: (a) a decrease in total REMsleep time relative to total sleep time by an amount greater than 5%; or(b) a decrease in total REM sleep time relative to total sleep time byan amount greater than 6.5%.

Embodiment 100, the pharmaceutical composition of any one of embodiments40, 41, 46, 47, 50, 56, 57, 60, and 61, wherein the pharmaceuticalcomposition when administered to a subject population provides apopulation geometric mean Tmax between about 4 hours and about 6 hoursafter administration.

Embodiment 101, a pharmaceutical composition in the form of a tablet,the tablet comprising,

amisulpride in the form of an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is from about 80:20 to about 88:12 by weight of freebase, and the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, isfrom about 100 mg to about 500 mg by weight of free base; and anextended release agent in an amount between about 10% and about 50% bytotal tablet weight.

Embodiment 102, the pharmaceutical composition of embodiment 101,wherein the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, isabout 200 mg by weight of free base and the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight of freebase.

Embodiment 103, the pharmaceutical composition of embodiment 102,wherein the tablet comprises: between about 35% to about 45% by totaltablet weight of amisulpride, between about 20% to about 40% by totaltablet weight of a pharmaceutically acceptable filler, and between about20% to about 30% by total tablet weight of the extended release agent.

Embodiment 104, the pharmaceutical composition of embodiment 103,wherein the extended release agent comprises hydroxypropylmethylcellulose.

Embodiment 105, the pharmaceutical composition of embodiment 104,wherein the hydroxypropyl methylcellulose has a median particle sizethat is 5-15 times larger than the median particle size of theamisulpride.

Embodiment 106, the pharmaceutical composition of embodiment 104,wherein the filler comprises D-mannitol and wherein the tablet comprisesbetween about 0.5% to about 2% by total tablet weight of a bindercomprising polyvinyl alcohol.

Embodiment 107, the pharmaceutical composition of embodiment 101,wherein the tablet comprises: a granular component admixed with anextra-granular component,

the granular component comprising amisulpride and a binder; and theextra-granular component comprising, an extended release agent.

Embodiment 108, the pharmaceutical composition of embodiment 107,wherein the granular component comprises one or more of (a) a filler;and (b) a binder.

Embodiment 109, the pharmaceutical composition of embodiment 108,wherein the granules comprise: (a) between about 60% to about 80% byweight of amisulpride, between about 10% to about 30% by weight offiller, and between about 1% to about 5% by weight of binder; or (b)between about 70% to about 80% by weight of amisulpride, between about20% to about 25% by weight of filler, and between about 1% to about 5%by weight of binder.

Embodiment 110, the pharmaceutical composition of embodiment 108,wherein the granular component comprises: between about 73% to about 78%by weight of amisulpride, between about 10% to about 12% by weight of aD-mannitol, between about 10% to about 12% by weight of a pregelatinizedstarch, and between about 1% to about 3% by weight of polyvinyl alcohol;based on the weight of the granular component.

Embodiment 111, the pharmaceutical composition of embodiment 107,wherein the extragranular component comprises one or more of (a) afiller; (b) a binder; and (c) a lubricant.

Embodiment 112, the pharmaceutical composition of embodiment 107,wherein the tablet (granules plus extragranular component) comprises:(a) between about 20% to about 70% by total tablet weight of granules ofextended release agent; or (b) between about 10% to about 50% by totaltablet weight of extended release agent.

Embodiment 113, the pharmaceutical composition of embodiment 107,wherein the tablet (granules plus extragranular component) comprises:(a) a combined amount of filler in both granular and extragranularbetween about 6% to about 60% by total tablet weight; or (b) a combinedamount of filler in both granular and extragranular between about 10% toabout 50% by total tablet weight.

Embodiment 114, the pharmaceutical composition of embodiment 107,wherein the tablet (granules plus extragranular component) comprisesbetween about 1% to about 2% by total tablet weight of a lubricant.

Embodiment 115, the pharmaceutical composition of embodiment 115,wherein the lubricant is magnesium stearate.

Embodiment 116, the pharmaceutical composition of embodiment 107,wherein the tablet (granules plus extragranular component) comprises:(a) between about 34% to about 39% by total tablet weight of aD-mannitol, and about 15% by total tablet weight of hydroxypropylmethylcellulose; or (b) between about 24% to about 29% by total tabletweight of a D-mannitol, and about 25% by total tablet weight ofhydroxypropyl methylcellulose; or (c) between about 4% to about 9% bytotal tablet weight of a D-mannitol, and about 45% by total tabletweight of hydroxypropyl methylcellulose.

Although the invention has been described with reference to a specificembodiment this description is not meant to be construed in a limitingsense. The invention being thus described, it is apparent that the samecan be varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications, alternatives, and equivalents as would be obvious toone skilled in the art are intended to be included within the scope ofthe following claims.

1. A method of treating bipolar depression comprising: administeringbetween about 200 mg to about 400 mg per day of amisulpride by weight offree base as a solid oral dosage form to a subject, the solid oraldosage form comprising amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is about 85:15 by weight offree base, and an extended release agent in an amount between about 10%to about 50% by total solid oral dosage form weight; wherein saidadministration provides a subject population average maximum QT intervalprolongation relative to baseline that is less than 12 milliseconds(ms).
 2. The method of claim 1, wherein said administration is once perday.
 3. The method of claim 1, wherein said solid oral dosage form is atablet.
 4. The method of claim 1, wherein the population average maximumQT interval prolongation relative to baseline is the population averagemaximum QTcF interval prolongation relative to baseline over the timeperiod of 12 hours after said administration.
 5. The method of claim 1,wherein the population average maximum QT interval prolongation relativeto baseline is less than 11 milliseconds (ms).
 6. The method of claim 1,wherein the population average maximum QT interval prolongation relativeto baseline is less than 10 milliseconds (ms).
 7. The method of claim 1,wherein said administration is about 200 mg per day of amisulpride byweight of free base.
 8. The method of claim 7, wherein the populationaverage maximum QT interval prolongation relative to baseline is lessthan 9 milliseconds (ms).
 9. The method of claim 1, wherein the extendedrelease agent comprises a matrix forming agent.
 10. The method of claim9, wherein the matrix forming agent comprises one or more cellulosicethers.
 11. The method of claim 1, wherein the extended release agent isin an amount between about 20% to about 40% by total solid oral dosageform weight.
 12. The method of claim 1, wherein the extended releaseagent comprises hydroxypropyl methylcellulose in an amount between about20% to about 30% by total solid oral dosage form weight. 13-15.(canceled)
 16. A method of treating bipolar depression comprising:administering between about 200 mg to about 400 mg per day ofamisulpride by weight of free base as a tablet to a subject, the tabletcomprising amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight of freebase, and an extended release agent in an amount between about 10% toabout 50% by total tablet weight; wherein said administration provides asubject population average maximum QT interval prolongation relative tobaseline that is less than about 0.4 milliseconds (ms) per 10 mg ofamisulpride.
 17. The method of claim 16, wherein said administration isonce per day.
 18. The method of claim 16, wherein the population averagemaximum QT interval prolongation relative to baseline is the populationaverage maximum QTcF interval prolongation relative to baseline over thetime period of 12 hours after said administration.
 19. The method ofclaim 16, wherein the population average maximum QT intervalprolongation relative to baseline is less than about 0.35 milliseconds(ms) per 10 mg of amisulpride.
 20. The method of claim 16, wherein thepopulation average maximum QT interval prolongation relative to baselineis less than about 0.3 milliseconds (ms) per 10 mg of amisulpride. 21.The method of claim 16, wherein the extended release agent comprises amatrix forming agent.
 22. The method of claim 21, wherein the matrixforming agent comprises one or more cellulosic ethers.
 23. The method ofclaim 22, wherein the extended release agent comprises hydroxypropylmethylcellulose in an amount between about 20% to about 40% by totaltablet weight.
 24. The method of claim 16, wherein said administrationprovides about 27 hours after said administration a subject populationaverage occupancy of dopamine D2 receptors between about 20% and about60%, when the occupancy of D2 receptors is measured using PositronEmission Tomography (PET) substantially as described in Table 38 andaccompanying text.
 25. The method of claim 16, wherein saidadministration provides a population Cmax/Cmin ratio of amisulpride thatis less than about 2, wherein the values of Cmax and Cmin are determinedwithin 9 hours after administration. 26-27. (canceled)
 28. A method oftreating bipolar depression comprising: administering between about 200mg to about 400 mg per day of amisulpride by weight of free base as asolid oral dosage form to a subject, the solid oral dosage formcomprising amisulpride in the form of an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight of freebase, and an extended release agent in an amount between about 10% toabout 50% by total solid oral dosage form weight; wherein saidadministration provides: a subject population average maximum QTcFinterval prolongation relative to baseline that is less than 12milliseconds (ms) over the time period of 12 hours after saidadministration, and about 27 hours after said administration a subjectpopulation average occupancy of dopamine D2 receptors between about 20%and about 60%.
 29. The method of claim 28, wherein said administrationis once per day.
 30. The method of claim 28, wherein said solid oraldosage form is a tablet.
 31. The method of claim 28, wherein theoccupancy of D2 receptors is measured using Positron Emission Tomography(PET) substantially as described in Table 38 and accompanying text. 32.The method of claim 28, wherein the extended release agent comprises amatrix forming agent.
 33. The method of claim 32, wherein the matrixforming agent comprises one or more cellulosic ethers.
 34. The method ofclaim 28, wherein the extended release agent comprises hydroxypropylmethylcellulose in an amount between about 20% to about 40% by totalsolid oral dosage form weight.
 35. The method of claim 28, wherein saidadministration provides a population Cmax/Cmin ratio of amisulpride thatis less than about 2, wherein the values of Cmax and Cmin are determinedwithin 9 hours after administration. 36-116. (canceled)